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• Assessing the non motor progression in PD: challenge or chimera?
  Roberto Erro
  Published on: 13 April 2016
• response to Erro
  Nico Weerkamp
  Published on: 13 April 2016

• Published on: 13 April 2016

  Assessing the non motor progression in PD: challenge or chimera?

  • Roberto Erro, Resident
  • Other Contributors:
    • Paolo Barone

  Dear Sir, We are pleased with the interest of Weerkamp in our work and are grateful for his comments, giving us the chance to comment the results of our study [1]. We would like to further thank him for having raised the issue of several scales which have been developed to assess the non-motor symptoms (NMS), but include such motor symptoms as morning dystonia and tremor on awakening. However, this is not the case here. I...

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  Dear Sir, We are pleased with the interest of Weerkamp in our work and are grateful for his comments, giving us the chance to comment the results of our study [1]. We would like to further thank him for having raised the issue of several scales which have been developed to assess the non-motor symptoms (NMS), but include such motor symptoms as morning dystonia and tremor on awakening. However, this is not the case here. Indeed, the NMS-Quest does not include such symptoms (nor they are discussed in our paper) and is likely to reflect a "pure" non-motor involvement [2]. With regard of the possible confounding interaction between the motor fluctuations and the NMS, it should be stressed that the NMS-Quest assesses the presence of NMS which patients might have experienced in the previous month. It is thereby very unlikely that the NMS-Quest may be severely affected by the pharmacological state. Nevertheless, it has been suggested that NMS may also fluctuate in more advanced stages of the disease. However, our patients were all evaluated in the on-state when assessed at follow-up and none of them had experienced motor fluctuations, as we have stated in our work. On the other hand, the reliability of the NMS-Quest in different pharmacological states has not been tested yet, and it may be interesting to further compare it with different scales, such as the Wearing-Off Questionnaires, which have been specifically developed for the non-motor fluctuations [3]. With regard of the study's design and the aim to assess the NMS progression, it should be noticed that, due to the efficacy of pharmacological treatment, evaluation of the natural progression of both motor and non-motor features of PD is nowadays impossible. Data on the natural short-term worsening of motor symptoms have been indeed obtained from patients in the placebo arms of controlled studies. To our knowledge, no placebo-controlled study has been developed so far regarding the whole NMS complex and its progression over the disease course and the dopaminergic therapy introduction. The work which has been mentioned by Weerkamp (the RECOVER study), neither included drug-naive PD patients at enrollment nor provided long-term outcomes regarding the NMS. It only showed the efficacy of 3-month lasting therapy with rotigotine on a few NMS (i.e. sleep disturbances, which in our opinion may partially reflect motor disturbances). This setting is far away from the clinical practice and from our first aim, which was to evaluate the NMS burden in the first 4 years of the disease over the dopaminergic therapy introduction. A control group of untreated patients would have given of course more informations to discuss, but this kind of study's design is impossible at present due to ethical issues. Assessment of the natural long-term progression of NMS over the whole disease course is indeed possible only by mean of comparisons of patients with and without L-Dopa and/or dopamine agonists. We finally want to thank Weerkamp for having brought to our attention the recently published article focusing on NMS progression [4], which unfortunately had not been published by the time of our submission. Antonini and colleagues attempted to evaluated the NMS progression and its relationship with quality of life in a large cohort PD patients. Although they used a different scale for the assessment of NMS and included more advanced (also fluctuating) patients with no informations regarding the dopaminergic therapy (for details, see the PRIAMO study), their findings are in line with our results and highlight the concept that NMS progression pursues different patterns and that the relationship between the dopaminergic therapy and the NMS improvement is not straightforward. This is further supported by the results of other studies evaluating the short-term effects of dopaminergic treatment on NMS in de novo PD patients [5]. Assessing the non-motor progression is currently one of the most exciting challenge of the research on PD: our results should serve as an incentive for planning future studies targeting the non motor disturbances. Given the absence of a reliable bio-marker which may be able to measure the underlying pathological progression, further clinical studies are needed to prospectively evaluate both NMS occurrence and severity and how they are modified by specific therapies.

  Roberto Erro, Paolo Barone.

  Reference [1] Erro R, Picillo M, Vitale C, et al. Non-motor symptoms in early Parkinson's disease: a 2-year follow-up study on previously untreated patients. J Neurol Neurosurg Psychiatry. 2013;84(1):14-7 [2] Martinez-Martin P, Schapira AH, Stocchi F, et al. Prevalence of nonmotor symptoms in Parkinson's disease in an international Setting; study using Nonmotor symptoms questionnaire in 545 patients. Mov Disord 2007;22:1623-9. [3] Stacy M. The wearing-off phenomenon and the use of questionnaires to facilitate its recognition in Parkinson's disease. J Neural Transm. 2010;117:837-46. [4] Antonini A, Barone P, Marconi R, et al. The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life. J Neurol. 2012;259:2621-31. [5] Kim HJ, Park SY, Cho YJ, et al. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J Neurol Sci 2009;287:200 -4.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 13 April 2016

  response to Erro

  • Nico Weerkamp, resident neurology
  • Other Contributors:
    • none

  Dear editor,

  With interest I read the article by Erro et al. in the January edition of JNNP (2013;84;14-17). The authors aim to assess nonmotor symptoms (NMS) in a cohort of newly diagnosed patients with Parkinson's disease (PD) with a subsequent follow up of two years. Meanwhile, treatment with (a combination of) levodopa, dopamine agonists or a MAO- inhibitor was started according to the movement disorder spec...

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  Dear editor,

  With interest I read the article by Erro et al. in the January edition of JNNP (2013;84;14-17). The authors aim to assess nonmotor symptoms (NMS) in a cohort of newly diagnosed patients with Parkinson's disease (PD) with a subsequent follow up of two years. Meanwhile, treatment with (a combination of) levodopa, dopamine agonists or a MAO- inhibitor was started according to the movement disorder specialist insight. The conclusion is that NMS are frequent, remain stable and only few NMS are influenced after two years of dopaminergic treatment. I agree with the authors that we know little about the effects of dopaminergic treatment on NMS. Some NMS may be dopa-responsive and in my opinion several items that appear in different nonmotor scales are in fact motor symptoms (morning dystonia, tremor on awakening, etc.). Therefore studies of this kind are needed. However, I find the conclusion of the current study problematic:

  1. The study's design: patients included in the study are assessed with the NMS-Quest and dopaminergic therapy is started 'ad libitum' (which indeed reflects clinical practice) and after two years patients are re- assessed with NMS-Q. It would have been much better when a control group was included in the study, because now the current manuscript does neither elucidate the natural course of NMS, nor does it demonstrate the effect of dopaminergic treatment. The authors report that NMS remain stable but we know nothing about disease progression. PD is a (sometimes fast) progressive disorder and it is known that both motor and nonmotor problems accumulate after only several years. Disease progression (both motor and nonmotor) may have been 'masked' by dopaminergic treatment but without a control group we really don't know. Another possibility would have been that patients were assessed with the NMSQuest after a much shorter follow up in order to assess treatment effects instead of disease progression. I believe that the current paper is a spin off of previous work published in JON which may explain the current set up of the study. 2. The authors report findings of the UPDRS part three but motor complications are not presented. How many patients were assessed in the on state when assesses at follow up with the NMS-Q? 3. Trenkwalder (Movement Disorders 2010) clearly showed that several NMS (early morning motor function particularly, but also the overall NMS burden) can be treated with the dopamine agonist rotigotine. This important study is unfortunately not mentioned in the article by Erro.

  Kind regards, Nico Weerkamp, Dept. of Neurology, Atrium Medical Center Heerlen, the Netherlands

  Henri Dunantstraat 5 6419 PC Heerlen, the Netherlands nicoweerkamp@hotmail.com

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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