The diagnosis and treatment of parkinson’s disease

7 Management of Parkinson’s Disease
Professor C E Clarke
Professor of Clinical Neurology, Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham and School of Clinical and Experimental Medicine, College of Medicine and Dental Sciences, University of Birmingham, Birmingham This review is based on the National Institute for Health and Clinical Excellence (NICE) guideline on the diagnosis and management of Parkinson's disease1 which will be updated in 2012. When to Start Treatment in Parkinson's Disease
Once Parkinson's disease has been diagnosed, any therapy which can slow or halt progression should be commenced immediately. Such neuroprotective or disease modifying therapy does not exist at present. Many agents have been investigated for neuroprotective properties in vitro and in vivo without success.1 Most clinicians delay the introduction of symptomatic treatment until the patient has significant functional disability, i.e. when it is interfering with activities of daily living, on the basis that symptomatic therapy is unlikely to be effective for mild symptoms which are not interfering with life. However, this view may change if it is found that early symptomatic treatment slows progression, as has been suggested.2 The results of the rasagiline delayed-start trials (TEMPO and ADAGIO)3-4 suggest that immediate treatment with a symptomatically active drug may have a disease modifying effect. Analogous findings in trials with levodopa (ELLDOPA)5 and selegiline (DATATOP)6 imply that any symptomatic therapy may have a disease modifying effect. However, a delayed-start design trial with the dopamine agonist pramipexole (PROUD) showed a symptomatic effect only. There are many reasons why we should be cautious in the interpretation of these trials:7-8 1. In TEMPO, the results with the 1 mg dose were not significant and in ADAGIO, the results with the 2 mg dose were not significant. There is also the possibility of selection bias in all delayed start trials, with a tendency to recruit milder slowly progressive patients who can tolerate no treatment for 18 months, so the results may not be generalisable. 2. The positive results of both TEMPO and ADAGIO were based on differences below 2 total UPDRS units. It has recently been shown that a clinically meaningful difference in total UPDRS in early Parkinson's disease is at least 6 units.9 3. This small benefit could be due to symptomatic non-specific effects on the musculoskeletal system rather than a true neuroprotective effect. The European Medicines Agency (EMA) requires evidence of an effect on a biomarker of disease progression as well as a clinical effect before it will give a product licence for neuroprotection. 4. Treating patients on diagnosis would increase the net cost of treatment. There is no evidence, at present, that this is a cost-effective policy change. 5. Treating patients earlier may result in more dopaminergic adverse reactions (i.e. nausea, vomiting, hypotension), along with impulse control disorders (e.g. pathological gambling, hypersexuality, punding). Earlier treatment may also expedite motor complications (i.e. dyskinesias and motor fluctuations. In conclusion, we must consider whether enough evidence has accumulated to change practice. If not, then we may need to perform further trials. Management of Early Parkinson's Disease
Once motor symptoms interfere with everyday life, the NICE guidelines recommend commencing an agent from one of three first line drug classes: levodopa, dopamine agonists or monoamine oxidase type B (MAOB) inhibitors (Table 1). Evidence from randomised controlled trials and systematic reviews supports the efficacy of each of these drug classes.1 It was previously not clear which class to choose in any given clinical situation. For instance, many adopted the policy of using a dopamine agonist in younger patients to delay the onset of motor complications (abnormal involuntary movements, end of dose wearing off and unpredictable ‘on’-‘off’ switching) which are more frequent if treatment is initiated with levodopa.1 However, levodopa treats motor symptoms better than dopamine agonists and many young patients may still require fine motor skills for work. Table 1 Options for initial symptomatic therapy for Parkinson’s disease (from ref 2)
Risk of side effects
Degree of symptom
Other adverse
complications
In an attempt to resolve this uncertainty, the Health Technology Assessment Programme funded the PD MED trial (www.pdmed.bham.ac.uk) which has been reported in abstract form.10 PD MED EARLY showed that levodopa was superior to levodopa-sparing therapy (with a dopamine agonist or MAOB inhibitor) in terms of patient-rated quality of life (using the Parkinson's Disease Questionnaire-39 scale) in spite of causing more dyskinesias. The size of the benefit of levodopa was clinically small, being equivalent to 6 months of disease progression on the PDQ-39 scale, but it was consistent across all age groups including younger patients. These results suggest that all patients should have levodopa as their initial therapy. With disease progression over several years, the dose will need to be steadily increased, but the dose should be restricted to avoid triggering off dyskinesias prematurely. For patients with an average body weight, the initial dose of levodopa will be 100 mg tds (with meals) which can be increased to 100 mg five times per day (additional doses with mid-morning and mid-afternoon drinks) and finally 600 mg per day (double dose with breakfast). Thereafter, dyskinesias and/or wearing off will require adjuvant therapy. Management of Later Parkinson's Disease
The majority of patients will eventually require levodopa, so motor complications are inevitable. At this stage, the NICE guidelines recommend adjuvant therapy to levodopa with either a dopamine agonist, a MAOB inhibitor or a catechol-O-methyl transferase (COMT) inhibitor (Table 2).1 A recent systematic review of all placebo controlled trials with these three drug classes suggested that the dopamine agonists and tolcapone were more effective than entacapone and MAOB inhibitors at reducing ‘off’ time and levodopa dose without an excess of side effects.11-12 However, this was based on indirect comparisons and in a predominantly younger patient population so the results may not be generalisable to all patients. Further evidence from head-to-head trials is required. Table 2 Options for adjuvant therapy in later Parkinson’s disease (from ref 2)
Risk of side effects
Degree of
complications
Other adverse events
The PD MED LATER trial randomised patients on levodopa with motor complications to any dopamine agonist, MAOB inhibitor or COMT inhibitor.13 The key finding was the large drug withdrawal rate due to adverse effects which was similar with all three drug classes. After one year of treatment, around 33% had stopped the allocated treatment, rising to 50% withdrawal after two years. There was no benefit in quality of life in using a dopamine agonist compared with a MAOB inhibitor or COMT inhibitor. However, there was weak evidence that the MAOB inhibitors may be superior to entacapone in quality of life, MMSE and the rate of development of dementia, although further follow up is required to confirm these findings. These results suggest that many patients will only be able to tolerate levodopa therapy and that attempts to introduce adjuvant agents should not be made. Further work from PD MED LATER should clarify which patients should avoid add-on therapy, but these are likely to be older patients and those with early signs of cognitive decline. There is still little evidence to direct the choice between adjuvant drug classes, but there is some suggestion in PD MED that an MAOB inhibitor should be tried first.13 There is no evidence comparing the efficacy of selegiline with rasagiline and the PD MED results seem to apply to both drugs. Selegiline should be tried first as it is less expensive, but switched to rasagiline if it is not tolerated. With disease progression, other adjuvant agents will be required, so many will have a dopamine agonist and a COMT inhibitor added at some point. This leads to ‘rational polypharmacy’ with medium dose levodopa and other adjuvant agents. In recent years, the ergot-derived dopamine agonists (i.e. bromocriptine, lisuride, pergolide and cabergoline) have been withdrawn from use in Parkinson's disease as they produce pleural, pericardial or peritoneal effusions and fibrosis and cardiac valvulopathy with pergolide and cabergoline. The non-ergot agonists (i.e. pramipexole, ropinirole and rotigotine) are less likely to produce such problems, but clinical experience has been much shorter. However, the non-ergot agonists do cause impulse control disorders which include pathological gambling, hypersexuality, punding (i.e. abnormal collecting and categorising behaviour). The DOMINION study found these in 14% of 3090 North American patients with Parkinson's disease.14 It is important to warn patients and their carers about these problems before drug initiation and to monitor for their occurrence throughout treatment. Management of Advanced Parkinson's Disease
Three randomised controlled trials were included in a Cochrane review of amantadine used to treat dyskinesias in later Parkinson's disease.15 Whilst the number of patients included was small (n=53) and the trials short, the NICE guidelines recommended that amantadine be used as an anti-dyskinesia agent.1 It is best to start with just 100 mg once daily, titrating up through 100 mg bd then 100 mg tds and to warn patients about the rare side effect of livedo reticularis (i.e. mottled brown rash on the legs). The dopamine agonist apomorphine is not effective orally due to extensive first-pass metabolism in the liver. It was developed as intermittent bolus injections to rescue patients from severe ‘off’ periods or as a subcutaneous infusion for patients with many ‘off’ periods. Both uses require continuous treatment with the antiemetic domperidone to prevent nausea and vomiting. Three small trials (n=56) documented the efficacy and safety of intermittent injections of apomorphine, but only observational studies are available for the continuous infusion.1 Nevertheless, the NICE guidelines approved both for use in treating motor complications which are intractable to changes in oral therapy. The NICE guidelines were prepared before the continuous infusion of a levodopa gel directly into the jejunum (Duodopa®) was licensed for the management of severe motor complications. Small trials showed that these infusions reduce ‘off’ time and improve motor function, activities of daily living, and quality of life.16-17 However, its use will be restricted by cost (£30,000 pa) and the need for a gastrostomy in potentially ill patients. In terms of which parenteral or surgical therapy to use in an individual patient, there are no head-to-head trials and few placebo controlled trials to guide such a choice.18 Therefore, decisions tend to be pragmatic and based on patient preference and treatment availability and cost: So, most patients elect for apomorphine infusion ahead of surgery, and in the NHS both must be considered before funding for levodopa gel infusion will be contemplated. Surgery (see Chapter 9)
Improved understanding of the neural mechanism of Parkinson's disease showed that the subthalamic nucleus (STN) is overactive.19 This led to the development of bilateral subthalamic (STN) stimulation surgery to switch off this nucleus. There have been many uncontrolled case series of STN stimulation, and only recently four randomised controlled trials (RCT)20-22 including the UK PD SURG trial. These showed that STN stimulation reduces ‘off’ time and ‘off’ time disability, so medication can be reduced, thereby reducing dyskinesia. Meta-analysis of the results of these RCTs shows a consistent improvement compared with deferred surgery at 6, 12 and 18 months of around 5 points in patient-rated quality of life (PDQ 39 summary index), a difference which has previously been shown to be clinically significant.9 The NICE guidelines recommended STN stimulation for patients with motor complications refractory to best medical treatment, who are biologically fit with no clinically significant active co-morbidity, who are levodopa responsive and have no clinically significant active mental health problems (depression or dementia).1 Questions still remain about the long-term safety of STN stimulation, as depression and suicide may be more common, and more information on cost-effectiveness of this expensive procedure is required. This should come from follow up of the PD SURG cohort. Non-motor Features of Parkinson's Disease (see Chapters 4 and 8)
The motor features of Parkinson's disease can be controlled reasonably well in most patients with the measures outlined above. It is the non-motor features of the disorder which now present the greatest management challenge, including dementia, psychosis, imbalance and falls, autonomic dysfunction, sleep disorders, and pain. The NICE guidelines found a paucity of treatment trials for non-motor features.1 What evidence there was related to mental health conditions, particularly dementia. The trial evidence to support the efficacy and safety of cholinesterase inhibitors for Parkinson's disease dementia was inadequate and further trials are required.1 Nursing and Allied Health Professional Interventions
Three randomised controlled trials assessed the efficacy of Parkinson's Disease Nurse Specialists
versus standard care.1 The benefits of nurses related to the overall patient care experience and delivery
of services rather than in outcome measures such as quality of life or health economics. Therefore, the
NICE guidelines recommended Nurse Specialists for clinical monitoring and medication adjustment,
a continuing point of contact for support, and a reliable source of information about clinical and social
matters for patients and carers.1
The evidence for the use of physiotherapy, occupational therapy and speech and language therapy in Parkinson's disease is based on a small number of trials with few participants, but clinical experience suggests that they are valuable.1, 23 The NICE guidelines concluded that all three interventions should be available to patients throughout the disease (Table 3). However, the NICE guidelines recommended that further large scale trials should be performed with these therapies, such as the ongoing UK PD REHAB trial (www.pdrehab.bham.ac.uk) and the PD COMM pilot trial. Table 3 Roles of allied health professional interventions in Parkinson's disease1
Physiotherapy
Gait re-education, improvement of balance and flexibility Improvement of functional independence, including mobility and activities of daily living Provision of advice regarding safety in the home environment Occupational therapy
Maintenance of work and family roles, home care and leisure activities Improvement and maintenance of transfers and mobility Improvement of personal self-care activities such as eating, drinking, washing and dressing Environmental issues to improve safety and motor function Cognitive assessment and appropriate intervention Speech and language Improvement of vocal loudness and pitch range, including speech therapy
therapy
programmes such as Lee Silverman Voice Treatment Teaching strategies to optimise speech intelligibility Ensuring an effective means of communication is maintained throughout the course of the disease, including use of assistive technologies Review and management to support the safety and efficiency of swallowing to minimise the risk of aspiration. Future Treatments
It is crucial that neuroprotective agents are found to slow or halt the progression of Parkinson's
disease. However, there are fundamental questions about neuroprotection trial design, particularly
delayed-start design trials7-8 and futility studies.24
Much effort has gone in to developing non-dopaminergic agents for parkinsonian symptoms and/or dyskinesias (e.g. the adenosine A2A receptor antagonist preladenant). However, many have proved disappointing in clinical trials, perhaps because the current toxin-based animal models do not truly reflect the underlying pathophysiology of Parkinson's disease.25 The prospect of neurorestoration with stem cell grafts continues to generate considerable attention. However, two trials of foetal midbrain grafts found that, whilst beneficial effects occur, severe ‘off’ period involuntary movements developed which necessitated pallidotomy in some cases.26-27 There have also been recent post mortem results from these early grafting trials showing the development of Lewy bodies in the grafts which suggests the pathological process in Parkinson's disease continues throughout life.28 It will be many years before stem cell implants are shown in large clinical trials to be free from tumour formation and capable of controlled dopamine release. In the meantime, various nerve growth factors may be shown to stimulate the development of remaining dopaminergic neurones.29 Competing interests: CEC received honoraria for lectures, travel expenses for conferences, and unrestricted
educational grants from Boehringer-Ingelheim, GlaxoSmithKline, Lundbeck, Orion Pharma, Novartis, Teva,
UCB.
Further Reading
NICE guidelines (http://www.nice.org/) Cochrane reviews (via National Library for Health or software.com/publications/cochrane/) Clarke CE. Parkinson's disease in Practice. Royal Society of Medicine Press: London. Second Edition. 2006. Information Resources
Parkinson's UK (http://www.parkinsons.org.uk/) European Parkinson's Disease Association (http://www.epda.eu.com/) Michael J Fox Foundation for Parkinson's disease research (http://www.michaeljfox.org/) References
1. National Collaborating Centre for Chronic Conditions. National Institute for Health and Clinical Excellence (NICE) Guidelines - Parkinson's disease: diagnosis and management in primary and secondary care. London: Royal College of Physicians; 2006. 2. Schapira A, Obeso J. Timing of treatment initiation in Parkinson's disease: a need for a reappraisal? Ann 3. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009 Sep 24;361(13):1268-78. 4. Parkinson Study Group. A controlled, randomised, delayed-start study of rasagiline in early Parkinson 5. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the progression of Parkinson's disease.[see comment]. N Engl J Med. 2004 Dec 9;351(24):2498-508. 6. Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol. 2002 May;51(5):604-12. 7. Clarke CE. Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed? Mov Disord. 2008 Apr 30;23(6):784-9. 8. Clarke CE, Patel S, Ives N, Rick C, Wheatley K, Gray R. Should treatment for Parkinson's disease start immediately on diagnosis or delayed until functional disability develops? Mov Disord. 2011 Jun;26(7):1187-93. 9. Schrag A, Sampaio C, Counsell N, Poewe W. Minimal clinically important change on the unified Parkinson's disease rating scale. Mov Disord. 2006 Aug;21(8):1200-7. 10. Gray R, Patel S, Ives N, Rick C, Jenkinson C, Wheatley K, et al. A large randomised trial assessing quality of life in patients with early Parkinson's disease: Results from PD MED EARLY. Parkinsonism and Related Disorders. 2012;18(Suppl 2):S32. 11. Stowe R, Ives N, Clarke CE, Handley K, Furmston A, Deane K, et al. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease. Mov Disord. 2011 Mar;26(4):587-98. 12. Stowe R, Ives N, Clarke CE, Deane K, Wheatley K, Gray R, et al. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications. Cochrane Database Syst Rev. 2010(7):CD007166. 13. Clarke C, Patel S, Ives N, Rick C, Jenkinson C, Wheatley K, et al. A large randomised trial assessing quality of life in patients with later PD: Results from PD MED LATER. Parkinsonism & Related Disorders. 2012;18(Suppl 2):S33. 14. Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010 May;67(5):589-95. 15. Crosby NJ, Deane KHO, Clarke CE. Amantadine for dyskinesia in Parkinson's disease (Cochrane Review). The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd; 2003. 16. Nyholm D, Nilsson Remahl AI, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease.[see comment]. Neurology. 2005 Jan 25;64(2):216-23. 17. Nyholm D, Askmark H, Gomes-Trolin C, Knutson T, Lennernas H, Nystrom C, et al. Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets. Clin Neuropharmacol. 2003 May-Jun;26(3):156-63. 18. Clarke CE, Worth P, Grosset D, Stewart D. Systematic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson's disease. Parkinsonism Relat Disord. 2009 Dec;15(10):728-41. 19. Crossman AR. Primate models of dyskinesia: the experimental approach to the study of basal ganglia- related involuntary movement disorders. Neurosci. 1987;21:1-40. 20. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al. A randomized trial of deep-brain stimulation for Parkinson's disease.[erratum appears in N Engl J Med. 2006 Sep 21;355(12):1289]. N Engl J Med. 2006 Aug 31;355(9):896-908. 21. Schupbach WM, Maltete D, Houeto JL, du Montcel ST, Mallet L, Welter ML, et al. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007 Jan 23;68(4):267-71. 22. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Jr., et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. 23. Deane K, Ellis-Hill C, Jones D, Whurr R, Ben-Shlomo Y, Playford E, et al. Systematic review of paramedical therapies for Parkinson's disease. Mov Disord. 2002;17:984-91. 24. Tilley BC, Palesch YY, Kieburtz K, Ravina B, Huang P, Elm JJ, et al. Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.[see comment]. Neurology. 2006 Mar 14;66(5):628-33. 25. Fox SH, Lang AE, Brotchie JM. Translation of nondopaminergic treatments for levodopa-induced dyskinesia from MPTP-lesioned nonhuman primates to phase IIa clinical studies: keys to success and roads to failure. Mov Disord. 2006 Oct;21(10):1578-94. 26. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease.[see comment]. N Engl J Med. 2001 Mar 8;344(10):710-9. 27. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease.[see comment]. Ann Neurol. 2003 Sep;54(3):403-14. 28. Olanow CW, Prusiner SB. Is Parkinson's disease a prion disorder? Proc Natl Acad Sci U S A. 2009 Aug 29. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.[see comment]. Ann Neurol. 2006 Mar;59(3):459-66.

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