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|Year : 2018 | Volume
| Issue : 6 | Page : 1853-1854
Management of advanced Parkinson disease: Still a riddle
Jayantee Kalita, Usha K Misra
Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||28-Nov-2018|
Dr. Jayantee Kalita
Department of Neurology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kalita J, Misra UK. Management of advanced Parkinson disease: Still a riddle. Neurol India 2018;66:1853-4
Parkinson disease (PD) is an age old disease, known as “Kampavata” in ancient literature Ayurveda, and as “shaking palsy” in the western world since the description by Galen in 175 AD. A detailed medical assay was published by James Parkinson in 1817. The low level of dopamine in the PD patients coincided with the discovery of dopamine. The dopamine miracle has been demonstrated in PD patients in 1961 following intravenous injection of 50-150mg of L-dopa. The bed-ridden PD patients started walking, the akinetic started becoming more mobile, and the voiceless, speechless and pallilelic became forceful and clearer. Thus, a theoretically-based research resulted in an amazingly straight-forward practical therapy. Since then, dopamine has been enjoying its key role in the treatment of PD.
The ‘honeymoon effect’ of L-dopa in PD patients starts wearing off after a few years. The therapeutic response of L-dopa in PD patients has 2 components: (1) The short duration response (SDR) is characterized by improvement in motor disability for a few hours after a single dose of levodopa; and, (2) the long duration response (LDR) is characterized by a sustained antiparkinsonian affect following a few days of L-dopa administration, which has been shown to last after even 2 weeks of L-dopa discontinuation., The SDR of L-dopa is masked by the LDR in the initial years of therapy, the patients enjoy a near-normal life and their disability does not touch the baseline.
After a few years of L-dopa therapy, the PD patients start experiencing a short motor response following each dose of LC (levodopa plus carbidopa), which is known as the “wearing off” phenomenon. At this stage, patients may develop peak dose dyskinesia (choreiform). The predictors of L-dopa induced dyskinesia are the doses of L-dopa, the severity and duration of PD, and the younger age of disease onset.
The basis of wearing off phenomenon, dyskinesia and behavioral abnormalities in PD has been a matter of debate. The mechanism is being shifted from the presence of a presynaptic defect to a post-synaptic one, or has been attributed to both. There is a steep rise and fall of dopamine levels following the oral intake of L-dopa due to an impaired capacity of the presynaptic terminal to store dopamine. The dynamic changes in the post-synaptic D2 receptors as well as impaired function of dopamine transporters may result in motor fluctuation. At this stage, a little increase in the dosage may induce peak dose dyskinesia, and reduction in the dose may result in motor block. The therapeutic options at this stage are addition of catechol-O-methyl transferase (COMT) inhibitors, mono-amino-oxidase (MAO)-B inhibitors and dopamine (D) 2 agonist on the one hand, and neurostimulation on the other. Selected PD patients may enjoy a second “honeymoon period” following neurostimulation.,,
The first line therapy in the PD patients manifesting with the ‘wearing off’ phenomenon are the COMT inhibitor medications, entacapone or tolcapone. A pooled analysis of 3 randomized double-blind placebo controlled trial on 551 patients experiencing the ‘wearing off’ phenomenon revealed an improvement in the Unified Parkinson Disease Rating Scale (UPDRS) score as well as the ‘on’ time, and a reduction in the ‘off’ time at 6 months. Both the LC (levodopa-carbidopa) and the LB (levodopa-benserazide) groups have benefited equally. The recommended use of COMT inhibitors at this stage is to reduce the dosage of levodopa by 15-25% in order to reduce the incidence of dyskinesias.
One of the articles in Neurology India reported the safety of entacapone with and without LC dose modification in the PD patients experiencing the ‘wearing off’ phenomenon. The patient global impression of change (PGI-C) improved in the group without LC modification, although objective parameters such as the UPDRS, Hoehn and Yahr stage, the ‘on’ time and the ‘off’ time were not significantly different between the two groups. The side effects including dyskinesia were also similar. The duration of PD and the dose of LC were widely variable in both the groups. The PGI-C is a subjective scale and may be influenced by the open labeled design of the study. The result needs to be cautiously interpreted in view of its open label design, lack of sample size calculation and lack of intention-to-treat analysis. Drug induced oromandibular dyskinesia is difficult to treat although choreiform movement may disappear after discontinuation of the offending drugs. Moreover, there may be an absorptive defect due to the degeneration of gastrointestinal dopaminergic neurons in the late stages of PD. Further randomized controlled trials are needed to evaluate the need for modification of the LC combination when COMT inhibitor is added, measuring their clinical benefit, side effects and relationship with the blood dopamine level. There may be a subset of PD patients vulnerable to peak dose dyskinesia in whom dose modification of LC may be essential. Identification of this group may further stratify the treatment benefit of PD patients during the wearing off period.
We thank Mr. Shakti Kumar for his secretarial help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, Olanow CW, Tanner C, Marek K; Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351:2498-508.
Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson's disease? Eur Neurol 2010;63:257-66.
Jenner P. Molecular mechanisms of L-DOPA-induced dyskinesia. Nat Rev Neurosci 2008;9:665-77.
Tanner CM. A second honeymoon for Parkinson's disease? N Engl J Med 2013;368:675-6.
Singh M, Shabari Girishan K V, Bajaj J, Garg K. Deep brain stimulation for movement disorders: Surgical nuances. Neurol India 2018;66, Suppl S1:122-30.
Doshi PK. Expanding indications for deep brain stimulation. Neurol India 2018;66, Suppl S1:102-12.
Kuoppamäki M, Leinonen M, Poewe W. Efficacy and safety of entacapone in levodopa/carbidopa versus levodopa/benserazide treated Parkinson's disease patients with wearing-off. J Neural Transm (Vienna) 2015;122:1709-14.
Park J, Kim Y, Youn J, Lee PH, Sohn YH, Koh SB, Lee JY, et al
. Levodopa dose maintenance or reduction in patients with Parkinson's disease transitioning to levodopa/carbidopa/entacapone. Neurol India 2017; 65:746-51.
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