Non-motor symptoms in Parkinson’s Disease: nature and burden

The impact of non-motor symptoms is gaining increased attention.  They are common, heterogeneous, and sometimes severe and disabling; and their more effective management is a major unmet need. Non-motor symptoms are given greater recognition in the latest Movement Disorders Society diagnostic and research criteria.

Although motor symptoms of resting tremor, bradykinesia, rigidity, and postural instability are primary features of PD, many patients experience non-motor symptoms (NMS) such as disorders of mood, cognition, sleep, and gastrointestinal function. It appears that certain NMS can precede by many years the development of motor symptoms; and in some patients they may remain the dominant features of the disease.

The nature and extent of NMS vary markedly between patients and according to disease stage, and perhaps according to etiology, if we accept that PD is in fact not a single entity but an umbrella term covering many different biological subtypes.2  On any understanding of the disease, control of NMS seems increasingly important to maintaining quality of life (Fig 1).

Burden: the voice of patients and carers

In the FDA’s recent Patient-Focused Drug Development Initiative, patients made the following points:3 PD impacts all aspects of their lives, limiting ability to work, care for themselves and others, and to maintain relationships. 

  • When asked to identify up to three symptoms with the greatest impact on daily life, the highest number of responses related to motor symptoms, followed by impaired balance and coordination, but then by cognitive impairment, and disturbed sleep.
  • Impaired balance and co-ordination was regarded as a major challenge, leading to falls and fear of falling.
  • Fatigue and constipation were also highlighted as problems.

Parkinson’s Disease is not just a disease of the brain, it is not just a disease of dopamine, and – above all -- it is not just a disorder of movement.

In a slightly earlier study of patients' perspectives, Marios Politis and colleagues from a group of London hospitals noted that patients and clinicians may differ in their views of what constitute the most troublesome symptoms.4 Among people who had had PD for more than six years, the greatest problem – in terms of quality of life -- was fluctuating response to medication, but this was followed by mood changes, drooling and sleep problems, and then by tremor. Problematic non-motor aspects of the disease such as pain and sleep, mood and bowel function were also frequent in patients who had had PD for fewer than six years.

NMS contribute to overall healthcare costs and have a profound impact on the quality of life of both patients and caregivers (Figs 1 and 2). Their improved management, including the development and use of non-dopaminergic therapies, has been identified as a major unmet medical need.5 The range and potential severity of NMS also argue strongly for the involvement of a multidisciplinary team and, in end-stage disease, for the integration of neurological and palliative care.5

Presentation

Non-motor symptoms in Parkinson’s Disease: nature and burden

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Figure 1: The burden of non-motor symptoms on the patient
Slide information
References

Non-motor symptoms of PD can be present for many years before the characteristic motor symptoms appear.[Duncan et al., 2014] These non-motor symptoms may affect an individual’s quality of life well before a formal diagnosis has been made.[Duncan et al., 2014] A study conducted in patients who were newly diagnosed with PD, found that their quality of life was reduced as the number of non-motor symptoms that were present increased.[Duncan et al., 2014]

Screening for non-motor symptoms at the time of diagnosis may prompt appropriate intervention, and reduce their negative impact on the patient’s quality of life.[Duncan et al., 2014]

Duncan GW, Khoo TK, Yarnall AJ, et al. Health-related quality of life in early Parkinson’s disease: the impact of nonmotor symptoms. Mov Disord 2014; 29 (2): 195–202.

Other reference used on slide:
Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 2009; 24 (15): 2175–2186.

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Figure 2: The burden of the cognitive symptoms of Parkinson’s disease on caregivers
Slide information
References

There are many aspects of PD that can intensify the caregiver burden (e.g., impaired movement, sleep disorders, pain, cognitive impairment, etc.).[Martinez-Martin et al., 2012]

Attentional deficits may have a negative impact on the ability of people with PD to perform basic everyday tasks, including physical and social activities.[Lawson et al., 2017] Consequently, caregivers may take on these responsibilities, further increasing the burden of care and reducing quality of life (which may already be considerably affected).[Lawson et al., 2017]

Researchers are hoping to determine the effects of caring for a person with PD on the cognitive function of the caregiver, as well as the potential impact that any such impairment might have on both parties.[Lawson et al., 2017]

Martinez-Martin P, Rodriguez-Blazquez C, Forjaz MJ. Quality of life and burden in caregivers for patients with Parkinson’s disease: concepts, assessment and related factors. Expert Rev Pharmacoecon Outcomes Res 2012; 12 (2): 221–230.

Lawson RA, Yarnall AJ, Johnston F, et al. Cognitive impairment in Parkinson’s disease: impact on quality of life of carers. Int J Geriatr Psychiatry 2017; 32 (12): 1362–1370.

View and download this and other slides on Epidemiology and burden of Parkinson's disease here.

In the pre-motor phase of PD, a range of NMS seems to be the norm, with olfactory impairment and REM sleep behavior disorder being particularly frequent.5 The possible value of a “prodromal signature” based on NMS and the relationship of such symptoms to our understanding of the complex etiology and staging of PD are considered in a companion article.

Interestingly, James Parkinson, in his seminal 1817 Essay on the Shaking Palsy, recognized that non-motor symptoms were also involved in the disease. “Sleep,” he wrote, “becomes much disturbed”. And the bowels, “which had been all along torpid, now, in most cases, demand stimulating medicines of very considerable power”. Although he could not explain how such a connection between brain and bowels might come about, Parkinson thought it possible that disorder of the gut could induce a “morbid action” and “derangement of structure” in the nervous system. 

Nature and prevalence of NMS

The Sydney Multicenter Study, which followed 136 people newly diagnosed with PD, provides a valuable insight into the nature and prevalence of NMS among long-term survivors.6  By twenty years, 100 had died. Of the 30 cohort members still alive (mean age 74 years), 83% had dementia, 74% experienced hallucinations, and 71% had urinary incontinence. Falls had occurred in 87%, and 48% experienced symptomatic postural hypotension.

One of the authors’ conclusions was that, in people with PD who survive sufficiently long, dementia is almost inevitable (although other authors subsequently reported somewhat lower rates - around 50% - of dementia on long-term follow-up7). Another was that the diverse features of advanced PD go far beyond lack of dopamine.

In the Sydney cohort, dementia was almost inevitable in PD patients followed for 20 years

In a prospective study of 113 people with PD (mean age 67; mean disease duration 5.7 years) attending two Montreal movement disorder clinics, Fereshtehnejad et al found hallucinations at baseline in 7-26% of patients.8 The proportion depended on disease subtype, which was subsequently defined by cluster analysis of clinical features and rates of progression. Hyposmia was present in 84-95% of patients, and mild but multidomain cognitive impairment in 21-67%.

Parkinson’s Disease is a multi-system condition which, in addition to motor symptoms, involves four major domains of NMS:

  • neuropsychiatric (including psychosis, depression, apathy, impaired cognition and dementia)
  • sleep-related
  • autonomic (including gastrointestinal, urinary and sexual dysfunction; and orthostatic hypotension), and
  • sensory (including pain and olfactory disturbance).

The prevalence of NMS differs depending on the population studied, varying with factors such as age and duration of disease, but also with the definitions used. However, there is consensus that such problems are frequent and contribute substantially to the overall burden of PD. Table 1 contains some representative estimates of prevalence.

In addition to the NMS that are intrinsic to PD, NMS can be induced or worsened to a greater or lesser extent by the use of anti-parkinsonian drugs.11 For example, impulse control disorders (ICDs) and sleep attacks are strongly associated with the use of dopamine agonist therapy. There are also emerging data pointing to differences in NMS profile between different ethno-geographic populations.12  

Table 1: Estimates of prevalence of non-motor symptoms in PD

Symptoms

Prevalence

Reference

Psychosis

50%

Goldman, Holden. Curr Treat Options Neurol 20149

Hallucinations

40%

Fénelon et al. Brain 200010

Delusions

5-10%

Goldman, Holden. Curr Treat Options Neurol 20149

Depression

15% to>50%

Politis et al. Mov Disord 20104; Obeso et al. Mov Dis 20171

Anxiety

30-40%

Obeso et al. Mov Dis 20171

Impaired cognition*

up to 67%

Fereshtehnejad et al. JAMA Neurol 20158

Dementia

30%, but up to 80% long term

Hely et al. Mov Dis 20086; Obeso et al. Mov Dis 20171

Constipation

40-50%

Borghammer et al. NPJ Park Dis 201714

Urinary tract dysfunction

27-85%

Borghammer et al. NPJ Park Dis 201714

Orthostatic hypotension

18%

Ha et al. Park Related Dis 201122

Olfactory

up to 90%

Obeso et al. Mov Dis 20171; Fereshtehnejad8; Doty26

REM Sleep Disorder

50%

St Louis et al. Mov Dis 201723

Impulse control disorders

46%

Corvol JC et al. Neurology30

*mild, multidomain

Neuropsychiatric symptoms

Associated with psychosis

In a classic paper based on the detailed assessment of 216 people with PD, Gilles Fénelon and colleagues found that 40% had experienced hallucinations – visual in the majority of cases – in the previous three months.10  The authors suggested that this high prevalence could not be explained solely as a side effect of chronic dopaminergic treatment: hallucinations can occur in newly diagnosed patients; and cognitive impairment and disturbances in the sleep-wake cycle were identified as important factors.

In a recent review, Goldman and Holden drew attention to adverse effects of both psychosis and dementia on the quality of life of PD sufferers and caregivers alike.9 The authors estimate that the prevalence of psychosis in PD is probably over 50%, and emphasize that psychosis and dementia are interlinked phenomena associated with increased need for nursing home placement and higher rates of morbidity and mortality. In 2018, Mahlknecht et al reported a 52% rate of hallucinations or delusions among a control group of PD patients followed for ten years in a study of deep brain stimulation.15  This provides support for the view that the lifetime prevalence of psychosis in PD is indeed around 50%. 

Genetic and other factors related to the risk of early PD-related psychosis are being identified. There appear to be racial or ethnic differences in susceptibility to hallucinations; and evidence for the involvement of cortical thinning is intriguing.16

Dementia and cognitive impairment

Cognitive impairment in people with PD often has a profoundly adverse effect on their carers

Progressive cognitive impairment affecting a wide range of domains is frequent7 and has recently been described as the most significant NMS associated with PD.1 Figure 2 provides details of the impact of cognitive dysfunction on those who care for people with PD. Cognitive deficits have been reported even in prodromal PD, and up to 80% of patients with a long history of the disease are thought to develop dementia. It has been estimated that 10% of people with PD develop the condition each year.9

The principal pathology is the diffuse presence of cortical Lewy bodies.1  The range of neurotransmitters involved in PD-associated cognitive impairment includes acetylcholine and norepinephrine, as well as dopamine. Glucocebrosidase (GBA) polymorphisms and mutations have recently been linked to increased risk of PD dementia.17

Anxiety and depression

Both disorders are likely to be due to a complex interplay between neurobiological factors and the psychological consequences of having a chronic, degenerative disease.18 In the case of depression, the former are said to include abnormalties of basotemporal limbic circuitry and a range of neurotransmitters such as norepinephrine, serotonin and dopamine.

Autonomic dysfunction

Lewy bodies are frequently found in the autonomic nervous system of people who die with PD, and autonomic dysfunction in various forms is a common part of PD symptomatology.19 Autonomic problems may become apparent in erectile and urinary dysfunction, for example. But these conditions are so closely related to age that it is not straightforward to disentangle the role of PD. However, the association of PD with gastrointestinal dysfunction – aspects of which may precede the onset of motor symptoms by many years – is both clear and intriguing.

Gastrointestinal dysfunction27

Radiotracer and imaging studies have shown extensive pathology of the sympathetic and parasympathetic nervous systems in people with PD.14 Disordered pharyngeal and esophageal motility is frequently evident, along with delayed gastric emptying and colonic transit.  Chaudhuri et al recently cited an estimate that more than 70% PD patients have GI disorders.5 These include gastric dysmotility and small intestinal bacterial overgrowth. In addition to the associated morbidity, gastroparesis has implications for the delayed absorption of oral drugs, notably levodopa.

A history of constipation is associated with an increased risk of PD, preceding diagnosis significantly more frequently in those who develop the disease than in matched controls.19,20

Orthostatic hypotension

The autonomic dysfunction associated with synucleinopathies can prevent sufficient  compensatory release of norepinephrine from sympathetic nerves, leading to hypotension on standing.21  In a study from Baylor College of Medicine, orthostatic hypotension was found in 18% of people with PD and its occurrence was associated with greater age, longer duration of parkinsonian symptoms, and more advanced Hoehn and Yahr stage.22

Lim and Lang recently considered whether orthostatic hypotension is intrinsic to PD or caused predominantly by treatment.11 They concluded that evidence of reflexive cardiovagal failure, sympathetic neurocirculatory failure and extracardiac noradrenergic denervation in a substantial proportion of untreated PD patients suggests it is part of the underlying disease process.

Orthostatic hypotension has significant effects on quality of life since falls and the fear of falls limit social and physical activity, and cardiac decompensation can lead to disability. In recognition of the importance of this problem, the American Autonomic Society and the National Parkinson Foundation recently issued joint recommendations on screening for orthostatic hypotension and its management.21

Idiopathic REM sleep behavior disorder looks like a very early manifestation of synucleinopathy

Sleep disorder

The majority of people with idiopathic REM sleep behavior disorder (RBD), characterized by a loss of atonia which allows complex motor behaviors including the acting out of dreams, will eventually be diagnosed with PD or a related synucleinopathy.23  St Louis et al cite a range of 40-90% among longitudinal series of RBD patients followed for six years or longer.  

As a prodromal feature, RBD probably has the greatest predictive power of the non-motor symptoms associated with PD. Also striking is the length of time by which the disorder can precede PD, which may not be diagnosed for several decades after the sleep problem becomes apparent.24

Estimating the prevalence of RBD in established PD is made difficult by differences in definition. However, a recent estimate suggests it is in the region of 25-30% in newly diagnosed patients and those with early disease.25

The view that RBD is early evidence of a widespread underlying synucleinopathy is supported by its association with other markers of neurodegeneration such as cognitive impairment, constipation, orthostatic hypotension, and hyposmia.23  

Olfactory dysfunction

Disorders of smell are another NMS closely associated with PD and predictive of its development. Doty estimates that around 90% of people with early PD experience olfactory dysfunction.26 This symptom is shared with many Alzheimer’s Disease patients, but is not as apparent in multiple system atrophy and progressive supranuclear palsy, making loss of smell potentially valuable as a means of distinguishing between parkinsonian syndromes. Hyposmia is also an NMS associated with diminished quality of life: among 750 consecutive patients attending a University of Pennsylvania smell and taste clinic, more than half reported adverse effects on psychological wellbeing.26

Up to 90% of people with early PD suffer loss of smell

New MDS criteria

While the new Movement Disorder Society Clinical Diagnostic Criteria retain bradykinesia plus rest tremor or rigidity as the core features of parkinsonism, they give new emphasis to non-motor aspects of the disease.28 This is intended to better reflect current understanding and diagnostic practice in expert centers.

Once parkinsonism has been documented, the judgement that PD is the cause relies on three categories of diagnostic features:

  • absolute exclusion criteria, which rule out PD (dementia has now been removed as an exclusion criterion for PD, even if it is the first presenting symptom)
  • red flags, which must be counterbalanced by additional supportive criteria to allow diagnosis of PD, and
  • supportive criteria ie positive features that increase confidence in the PD diagnosis.

Loss of olfaction is one such supportive feature. The other side of the coin is that absence of any common NMS (despite at least five years’ disease duration) is regarded as a red flag. The relevant NMS include RBD, constipation, symptomatic orthostasis, and psychiatric dysfunction (depression, anxiety or hallucinations).

Non-motor features were regarded as especially important in the development of the MDS’s companion set of  criteria for prodromal PD.29 These criteria are intended at least initially for use in a research context but acknowledge that PD pathology and related symptoms involve the peripheral nervous system and non-dopaminergic brain structures. The likelihood of prodromal PD is calculated based on age, environmental and genetic risk factors, biomarkers (eg dopaminergic imaging) and prodromal symptoms and signs such as constipation and hyposmia.

References
  1. Obeso JA, Stamelou M, Goetz CG, et al. Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord. 2017;32(9):1264‑1310.
  2. Espay  AJ, Lang AE. Parkinson Diseases in the 2020s and Beyond: Replacing Clinico-Pathologic Convergence With Systems Biology Divergence. J Parkinsons Dis. 2018; 8(Suppl 1): S59–S64.
  3. The Voice of the Patient: A series of reports from the U.S. Food and Drug Administration’s Patient-Focused Drug Development Initiative. Parkinson’s Disease. April 2016, last updated May 2016.
  4. Politis M, Wu K, Molloy S, et al. Parkinson's disease symptoms: the patient's perspective. Mov Disord. 2010 Aug 15;25(11):1646‑1651.
  5. Chaudhuri KR, Bhidayasiri R, van Laar T. Unmet needs in Parkinson's disease: New horizons in a changing landscape. Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S2-S8.
  6. Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord. 2008;23(6):837-844.
  7. Coelho M, Marti MJ, Tolosa E, et al. Late-stage Parkinson’s disease: the Barcelona and Lisbon cohort. J Neurol 2010;257:1524-32.
  8. Fereshtehnejad SM, Romenets SR, Anang JB, et al. New Clinical Subtypes of Parkinson Disease and Their Longitudinal Progression: A Prospective Cohort Comparison With Other Phenotypes. JAMA Neurol. 2015 Aug;72(8):863-873.
  9. Goldman JG, Holden S. Treatment of Psychosis and Dementia in Parkinson’s Disease. Curr Treat Options Neurol. 2014;16(3):281.
  10. Fénelon G, Mahieux F, Huon R, et al. Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Brain. 2000;123:733-
  11. Lim S-Y, Lang AE. The Nonmotor Symptoms of Parkinson’s Disease—An Overview. Movement Disorders. 2010;25(Suppl. 1):S123–S130
  12. Lim SY,Tan AH, Annuar AA et al. Parkinson’s disease in the Western Pacific Region. Lancet Neurology 2019;18:865-879
  13. Muntean ML et al. REM sleep behavior disorder in Parkinson’s Disease. J Neural Transm 2014 Mar 22
  14. Borghammer P, Knudsen K, FedorovaTD, et al. Imaging Parkinson’s disease below the neck. NPJ Parkinsons Dis. 2017;3:15
  15. Mahlknecht P et al. Has deep brain stimulation changed the natural history of Parkinson’s disease? A case control longitudinal study. EAN, Lisbon 2017. Abstract TCLIN05
  16. Ffytche DH et al. Risk factors for early psychosis in PD: insights from the Parkinson's Progression Markers Initiative. J Neurol Neurosurg Psychiatry. 2017 Apr;88(4):325-331.
  17. Lunde KA, Chung J, Dalen I et al. Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease. Alzheimers Dement. 2018 Oct;14:1293-1301.
  18. Marsh L. Depression and Parkinson’s Disease: Current Knowledge. Curr Neurol Neurosci Rep. 2013 Dec; 13(12): 409.
  19. Savica R, Carlin JM, Grossardt BR et al. Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009;73(21):1752-1758.  
  20. Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet Neurol. 2015;14(1):57-64.
  21. Gibbons CH, Schmidt P, Biaggioni R et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017; 264:1567–1582.
  22. Ha AD, Brown CH, York MK, Jankovic J. The prevalence of symptomatic orthostatic hypotension in patients with Parkinson's disease and atypical parkinsonism. Parkinsonism Relat Disord. 2011 Sep;17(8):625-8. doi: 10.1016/j.parkreldis.2011.05.020.
  23. St Louis EK, Boeve AR, Boeve BF. REM Sleep Behavior Disorder in Parkinson's Disease and Other Synucleinopathies. Mov Disord. 2017 May;32(5):645-65.
  24. Claassen DO, Josephs KA, Ahlskog JE, et al. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology. 2010;75(6):494–499.
  25. Muntean ML, Sixel-Döring F, Trenkwalder C. REM sleep behavior disorder in Parkinson's disease. J Neural Transm. 2014 Mar 22. PMID: 24658661 DOI: 10.1007/s00702-014-1192-4
  26. Doty RL. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol. 2012 May 15;8(6):329‑339.
  27. Fasano A, Visanji NP, Liu LW et al. Gastrointestinal dysfunction in Parkinson’s Disese. Lancet Neurol. 2015 Jun;14(6):625-39. doi: 10.1016/S1474-4422(15)00007-1.
  28. Postuma RB et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015; 30: 1591-601.
  29. Berg D et al.  MDS research criteria for prodromal Parkinson's disease. Mov Disord 2015; 30: 1600-11.
  30. Corvol JC, Artaud F, Cormier-Dequaire F et al. Longitudinal analysis of impulse control disorders in Parkinson disease. Neurology 2018;91: e189e201
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