Review
Parkinson’s disease: The non-motor issues

https://doi.org/10.1016/j.parkreldis.2011.02.018Get rights and content

Abstract

Non-motor symptoms (NMS) of Parkinson's disease remain the most under-appreciated and under-researched when taken as a whole. Data is emerging that it is the “totaL” burden of NMS that is the major determinant of quality of life not a single NMS such as depression for instance. Only recently validated tools such as the NMSQuest which empowers patients to declare NMS and the NMS scale, the SCOPA scales, and the modified version of the MDS-UPDRS have become available and validated for bedside clinical assessment of NMS. For the first time clinical trials have been incorporating non-motor measures as outcome measures and clinical recommendations for treatment of non-motor symptoms of PD are being published. This review aims to address some of these topical and “real life” aspects of modern day management of Parkinson's.

Introduction

James Parkinson did not consider Parkinson’s disease (PD) to be a motor disorder alone and in 1817, he referred to sleep disturbance, constipation, dysarthria, dysphonia, dysphagia, sialorrhoea, urinary incontinence and, ‘at the last, constant sleepiness with slight delirium’ in his ‘Essay on the Shaking Palsy’ [1]. We, in the movement disorders community have been somewhat oblivious of this fact and focused our research and energy largely on motor aspects of Parkinson’s. As such most endpoints in clinical trials address motor endpoints (UPDRS and dyskinesias) while the UK PD Brain Bank criteria for diagnosis of Parkinson’s does not include any non-motor features [2]. However, what is irrefutable is that in PD, non-motor symptoms (NMS) occur in over 90% of patients across all stages and include a range of symptoms from neuropsychiatric and autonomic dysfunction to sleep disturbance and poorly understood and reported sensory symptoms such as pain and vision (Table 1, Table 1B, Table 2, Table 3) [3], [4], [5], [47], [48], [49], [50]. NMS does correlate with advancing disease, and this is the commonly perceived notion, but some such as REM behaviour disorder (RBD) and olfactory deficit precede the onset of motor symptoms by a number of years [6]. Even though commonly appreciated, it is only recently that a body of data has emerged suggesting that the burden of NMS has a key negative impact on quality of life (QoL) [4], [6], [51], more profound than the motor aspects of Parkinson’s [7]. A most recent example is a recently published international study of 411 PD patients [52]. International studies also suggest that NMS often remain undiagnosed and therefore, untreated [5], [8].

Section snippets

Pathophysiology

The common clinical perception is that several NMS have a relatively poor response to dopaminergic therapy and thus pathophysiology involving the serotonergic and noradrenergic ones are involved [9]. The concept of a six stage pathological process based on Lewy body formation has been described by Braak and colleagues, beginning at induction sites with degeneration of the olfactory bulb and the anterior olfactory nucleus (clinically manifest as olfactory dysfunction) at stage 1 while stage

Extra nigral pre-motor pathophysiology

Hawkes with Braak have posited the “dual hit” hypothesis for pathogenesis of PD where they propose an infective basis for PD suggesting that a viral neurotropic agent enters the brain via the nasal (anterograde transmission to temporal lobe) and gastric (retrograde transmission to medulla via the Meissner’s plexus and vagal neurones) routes [12]. An infectious basis of Parkinsonism has been suggested in the past by Calne and Lees and others [14], [15] Strong evidence points towards sporadic PD

Pre-motor Parkinson’s disease

Based on the work published by Braak and others it is now recognised that NMS of PD can present at any stage of the disease but is present during the “pre-motor stage” [11], [12], [48].

Prospective data from several works suggest that at least four distinct NMS of PD such as olfactory problems, rapid eye movement behaviour disorder (RBD), constipation and depression may predate the motor signs [17], [18], [19], [20]. NMS also occurs in the late stage of PD as reported in the 20-year follow up

Prevalence of non-motor symptoms of PD

To date, only three complete prevalence studies of NMS have been reported in literature (Table 2), one national and one international and reflect the difficulties amongst researchers to acknowledge the whole burden of NMS in PD by composite studies as there is a wide range of NMS. This is reflected in the fact that there are a considerable number of studies which have addressed prevalence of specific NMS in PD such as depression, dementia, or sleep dysfunction. In part this is related in the

NMS of PD are frequently unrecognized

Healthcare professionals still often ignore or perhaps chose not to discuss NMS in clinic consultations. This was first reported by in a prospective study of 101 patients by Shulman and colleagues who reported that neurologists failed to identify major NMS such as depression, sleep disturbances, anxiety and fatigue in more than 50% of the patients [27]. NMS can easily be missed as clinic consultations focus largely on the motor aspects of PD and additionally, physicians may be unaware that NMS

The “holistic” tools for assessment of NMS of PD

Until 2006, non-specific measures were used to assess NMS domains such as sleep, mood and cognition, unsupported by appropriate validation studies in the PD population. In the last decade, however, several initiatives (Scales for Outcomes in PD (SCOPA); Parkinson’s disease non-motor group (PDNMG); and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)) have developed a set of specific NMS measures for application in clinical practice and research.

The PDNMG has led

Non-motor fluctuations in response to dopaminergic therapy

Non-motor fluctuations may co-exist with motor fluctuations and have been classified to three subtypes, dysautonomic, cognitive/psychiatric and sensory/pain [37], [38]. The cause appears to be secondary to pulsatile dopaminergic therapy similar to pathogenesis of motor fluctuations.

Anxiety (66%), drenching sweats (64%), slowness of thinking (58%), fatigue (56%), and akathisia (54%) were the most frequent non-motor fluctuations in a study by Witjas et al. [38] and these correlated with the motor

NMS and quality of life

NMS appears to be the key determinant of HRQoL impairment in PD, both as a direct consequence of symptoms (e.g. depression, sleep dysfunction are determinants of HRQoL) and also indirectly, because of the disability caused by NMS [2], [4], [6], [40], [41]. In two large international studies involving over 600 patients, scores from the unified NMS Scale were associated in the most robust manner with those from a PD-specific HRQoL measure (PDQ-8 and PDQ-39) [4], [6]. The evidence is compelling as

Treatment strategies: are NMS of PD untreatable?

Therapeutic nihilism exists when treatment of NMS is considered and to many, surprisingly even movement disorders specialists NMS of PD are non-dopaminergic and in essence, not directly related to PD. This may explain the non-declaration of NMS by patients and the lack of any NMS being considered in the so called “gold standard” clinical trials of dopaminergic agents relying on motor endpoints as the primary outcome variable. Only recently, this trend has been buckled and the RECOVER study is

Conclusions

Parkinson’s disease presents in a heterogeneous manner and non-motor symptoms are common in patients with PD although these remain under-reported and they are often overlooked as clinicians are focused on motor features which are easier to manage with a reasonable evidence base for treatment [54], [55]. However, it is the burden of NMS that result in significant negative impact on quality of life for the patient and most often, the carer. In spite of a range of NMS of PD that appear to have a

Acknowledgements

All members of EUROPAR (Cristian Falup-Pecurariu, David Brooks, Daag Aarsland, Claudia Trenkwalder, J J van Hilten, Tove Henriksen, Graeme MacPhee, Alexandra Rizos, Anne Martin, Yogini Naidu, Susanne Tluk). Alexandra Rizos for editing and stylistic revision.

References (55)

  • Y. Naidu et al.

    Efficacy of apomorphine infusion on mood and depression aspects of non-motor symptoms in advanced Parkinson’s disease

    Parkinsonism Relat Disord

    (2009)
  • Z. Qin et al.

    Health related quality of life in early Parkinson’s disease: impact of motor and non-motor symptoms, results from Chinese levodopa exposed cohort

    Parkinsonism Relat Disord

    (2009)
  • D. Calne

    A definition of Parkinson’s disease

    Parkinsonism Relat Disord

    (2005)
  • G. Alves et al.

    Epidemiology of Parkinson’s disease

    J Neurol

    (2008)
  • K.R. Chaudhuri et al.

    Early Parkinson’s disease and non-motor issues

    J Neurol

    (2008)
  • P. Martinez-Martin et al.

    International study on the psychometric attributes of the non-motor symptoms scale in Parkinson disease

    Neurology

    (2009)
  • K.R. Chaudhuri et al.

    The non declaration of non motor symptoms of Parkinson’s disease to healthcare professionals. An international survey using the NMSQuest

    Mov Disord

    (2010)
  • K.R. Chaudhuri et al.

    The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: results from an international pilot study

    Mov Disord

    (2007)
  • A. Schrag et al.

    What contributes to quality of life in patients with Parkinson’s disease?

    J Neurol Neurosurg Psychiatr

    (2000)
  • D.J. Zgaljardic et al.

    Cognitive and behavioural dysfunction in Parkinson’s disease: neurochemical and clinicopathological contributions

    J Neural Transm

    (2004)
  • H. Braak et al.

    Staging of brain pathology related to sporadic Parkinson’s disease

    Neurobiol Aging

    (2003)
  • C. Hawkes et al.

    Parkinson’s disease: a dual hit hypothesis

    Neuropathol Appl Neurobiol

    (2007)
  • C.H. Hawkes et al.

    Olfactory disturbance in Parkinson’s disease

    J Neurol Neurosurg Psychiatr

    (1997)
  • J.P. Hubble et al.

    Nocardia species as an etiologic agent in Parkinson’s disease: serological testing in a case-control study

    J Clin Microbiol

    (1995)
  • D.B. Calne et al.

    Late progression of post-encephalitic Parkinson’s syndrome

    Can J Neurol Sci

    (1988)
  • G.L. Willis

    Parkinson ’s disease as a neuro-endocrine disorder of circadian function: dopamine melatonin imbalance and the visual system in the in the genesis and progression of the degenerative process

    Rev Neurosci

    (2008)
  • R.D. Abbott et al.

    Frequency of bowel movements and the future risk of Parkinson’s disease

    Neurology

    (2001)

    • Cited by (311)

    • Executive dysfunction and cognitive decline, a non-motor symptom of Parkinson's disease captured in animal models

      2024, International Review of Neurobiology

    • Computerized analysis of hypomimia and hypokinetic dysarthria for improved diagnosis of Parkinson's disease

      2023, Heliyon

    • Deep learning and wearable sensors for the diagnosis and monitoring of Parkinson's disease: A systematic review

      2023, Expert Systems with Applications

    • Ampakine CX614 increases respiratory rate in a mouse model of Parkinson's disease

      2023, Brain Research

    • Gait Data-Driven Analysis of Parkinson’s Disease Using Machine Learning

      2024, EAI Endorsed Transactions on Pervasive Health and Technology

    • High-frequency multimodal training with a focus on Tai Chi in people with Parkinson’s disease: a pilot study

      2024, Frontiers in Aging Neuroscience
    View all citing articles on Scopus
    View full text
    Copyright © 2011 Published by Elsevier Ltd.