Many Faces of Parkinson’s Disease: Non-Motor Symptoms of Parkinson’s Disease

Article information

J Mov Disord. 2015;8(2):92-97
Publication date (electronic) : 2015 May 31
doi : https://doi.org/10.14802/jmd.15003
Department of Neurology, Korea University College of Medicine at Guro Hospital, Seoul, Korea
Corresponding author: Seong-Beom Koh, MD, PhD, Department of Neurology, Korea University College of Medicine at Guro Hospital, 148 Gurodong-ro, Guro-gu, Seoul 152-703, Korea Tel: +82-2-2626-3169 Fax: +82-2-2626-1257 E-mail: parkinson@korea.ac.kr
Received 2015 January 28; Revised 2015 January 28; Accepted 2015 February 12.

Abstract

Parkinson’s disease (PD) is a multi-systemic disorder that is characterized by a combination of motor and non-motor symptoms (NMS). The dopaminergic neurodegeneration of PD is involved in the genesis of NMS, but other conditions and side effects of levodopa are also associated with NMS. NMS can develop at all stage of PD and rapid eyeball movement sleep behavior disorder (RBD), constipation, depression, and olfactory dysfunction are considered prodromal signs of PD. Many NMS related with motor deficits and cognitive dysfunction. Some NMS including olfactory dysfunction, RBD and abnormal stereopsis are associated with presence of other NMS of PD. In addition, several NMS can be helpful to differentiate between idiopathic PD and other parkinsonian disorders. Early recognition and management of NMS in PD patients is important for preserving quality of life.

INTRODUCTION

Parkinson’s disease (PD) is considered a multi-systemic neurodegenerative disorder that is characterized by a combination of motor and non-motor symptoms (NMS) [1,2]. For a long time the main clinical focus in PD has been on the motor symptoms, however, there is increasing recognition that the clinical spectrum of PD is more extensive, also including NMS. NMS of PD comprised a variety of cognitive, neuropsychiatric, sleep, autonomic, and sensory dysfunctions [3]. Neuroanatomically, NMS may be subdivided into cortical manifestations (psychosis and cognitive impairment), basal ganglia symptoms (impulse control disorders, apathy, and restlessness or akathisia), brainstem symptoms (depression, anxiety, and sleep disorders), and the peripheral nervous system disturbances [orthostatic hypotension (OH), constipation, pain, and sensory disturbances] [4]. Another way of classifying NMS is to divide it by the contributing factors [5,6]. Some NMS correlated with accumulation of Lewy body pathology and disease severity [3,5] and other NMS are known as dopamine replacement therapy related symptoms [7,8]. Additionally, some NMS including rapid eyeball movement sleep behavior disorder (RBD), constipation, depression and olfactory dysfunction can be present in prodromal PD [9]. Recently NMS are recognized as an important part of PD symptoms which is a significant cause of disability and poor quality of life for PD patients and receiving medical attention as a focus of care [10-12]. This manuscript will review the literature on NMS and provide some educational issues about NMS of PD and other parkinsonian disorders.

SCALES FOR NMS ASSESSMENT

The assessment of NMS in patients with PD is essential for proper management. There are specific validated tools available for their assessment. The Unified Parkinson’s Disease Rating Scale is an easyto-use instrument and extensively applied to clinical trials of early PD [13]. It includes a few items for NMS but has a limited application because it reliably completed by non-demented patients. The Scale for Outcomes in Parkinson’s disease (SCOPA) battery of assessments consists of seven sub-rating scales that cover almost all symptom domains of PD (PROfiling PARKinson’s disease or PROPARK) (http://www.scopa.propark.eu). It was designed to be short, practical to administer, and either self-assessed or observer-administered. The non-motor symptoms questionnaire (NMSQ) is a self-administered screening tool comprising 30 items of NMS [14]. It is used to identify presence of NMS for further investigation and does not provide a severity of symptoms and an overall score. The non-motor symptoms scale (NMSS) is observer-rated scale consists of 9 domains, 30 items [15]. It was designed to quantify clinically significant NMS by measuring the frequency and severity of NMS. The NMSS translated into Korean exhibited good validity for the assessment of NMS in Korean PD patients [16].

NMS AS PREMOTOR SYMPTOMS

Many studies suggest there is a prodromal or premotor stage of PD before the onset of motor symptoms. Because the early occurrence of NMS correlates with the progression of Lewy body pathology [17] and even dopaminergic cell loss in subtantia nigra occurs from the premotor stage [18], identifying early PD as a target of neuroprotective treatment is spotted. Some NMS including olfactory dysfunction, RBD, constipation, and depression may precede the development of motor symptoms of PD and are considered prodromal signs before diagnosis of classical PD [9,19]. In addition, visual changes, autonomic dysfunction, and subtle cognitive changes may also be present at prodromal stages of PD [9].

RELATIONSHIP BETWEEN NMS AND DOPAMINE REPLACEMENT THERAPY

The motor symptoms can be classified with the levodopa responsiveness. Bradykinesia and rigidity are most likely to get better with levodopa, while axial problems such as balance, speech and gait disturbance do not show adequate response to levodopa compared to bradykinesia and rigidity. In the same manner, NMS can be classified with the relationship of dopaminergic treatment (Table 1) [20,21]. Recent positron emission tomography study suggests a dopaminergic contribution to some NMS [22] and such symptoms related to the dopamine replacement therapy (DRT). Because levodopa may modify striatal serotonin level [23], some non-dopaminergic NMS also respond to DRT. However, many NMS occur as a result of dysfunction of various neurotransmitters, they require different treatments rather than DRT.

Non-motor symptoms of Parkinson’s disease and their responsiveness to dopamine therapy [26]

RELATIONSHIP BETWEEN NMS AND MOTOR SYMPTOMS

The postural instability gait difficulty (PIGD) subtype of PD has been reported to be associated with NMS. Patients with the PIGD subtype were related to faster cognitive decline [24] and more frequent depression [25]. Recent study suggests that patients with higher scores of motor symptom experienced greater numbers of NMS and among them, patients with the PIGD subtype had higher NMSQ scores than patients with other subtypes [26]. Fluctuation of motor symptoms in PD also has relation to NMS. PD patients with motor fluctuation were related with more anxiety [25]. Anxiety, depression, fatigue, inner restlessness, pain, concentration/attention and dizziness were known to fluctuate in conjunction to motor fluctuations with more frequent and severe symptoms in ‘off’ compared to ‘on’ state [27]. The patterns of these NMS fluctuations are heterogeneous and complex, but psychic NMS fluctuate more frequently and severely [27]. However, the study revealed no correlation between the severity of NMS and motor function [27]. In addition, there is a close relationship between sensory dysfunction and motor signs. Higher-order discriminative sensory dysfunction seems to contribute in part to the development of axial motor deficits in PD [28]. The discriminative sensory dysfunction and consequent abnormal sensorimotor integration seem to be involved in the impaired finger dexterity (coin rotation test) of PD [29]. A study on dysfunction of special sensory in early PD patients revealed postural instability caused by sensory organization defects (visual & vestibular processing) seem to be related with motor deficits and cognitive dysfunction [30].

INTERRELATIONSHIP AMONG NMS

Several studies have reported the interrelationship among some NMS. Olfactory dysfunction in PD was known to be related to both cardiac sympathetic and parasympathetic dysfunction measured by the heart/mediastinum ratio of cardiac 123I-MIBG uptake, the fall in orthostatic blood pressure, and heart rave variability [31]. Olfactory dysfunction was also associated with postganglionic cardiac and organ-selective extracardiac noradrenergic denervation as indicated by concentration ratios of 6-[18F] fluorodopaminederived radioactivity in heart versus other organs and by low concentrations of norepinephrine and dihydroxyphenylglycol levels in skeletal muscle microdialysate samples [32]. One study suggested that PD patients with RBD were at higher risk of manifesting hallucinations and delusions [33]. However, the other study reported that the presence of RBD was associated with symptoms, signs and prevalence of OH but not associated with psychotic symptoms [34]. Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment and autonomic dysfunction [33,35]. Cognitive impairment is also related to neurocirculatory abnormalities, especially OH and supine hypertension in early PD [36]. PD patients with abnormal stereopsis showed more frequent abnormal visual perception and constructive function compared to patients with normal stereopsis [37]. Abnormal stereopsis is associated with nondominant extrastriate cortical atrophy and that it implicates the cortical visual dysfunction as part of the nonmotor symptoms in PD [38].

Cognitive impairments are common in PD. Despite its clinical importance, the development of dementia is still difficult to predict. Vivid dreaming, RBD, hyposmia, abnormal stereopsis, and depression were significant NMS PD dementia predictors at 24 months in one study [39]. These NMS are also associated with a more rapid rate of cognitive decline.

NMS IN OTHER PARKINSONIAN OR MOVEMENT DISORDERS

Non-motor symptoms has been investigated in other neurodegenerative disorders associated with parkinsonism. Olfactory dysfunction corresponds to neuropathological findings of Lewy bodies in the anterior olfactory nucleus [40]. Olfactory dysfunction tested by the University of Pennsylvania smell identification test (UPSIT) was found to be mildly impaired in multiple system atrophy (MSA) [41,42], and normal in progressive supranuclear palsy (PSP) [41], corticobasal degeneration [41,42], and vascular parkinsonism [43]. The UPSIT was moderately sensitive and specific for differentiation of idiopathic PD from other parkinsonian syndrome but less specific for distinguishing idiopathic PD from MSA [44]. Instead, early presentation of autonomic failure, sleep problems and respiratory dysfunctions/stridor are regarded as premotor signs for diagnosis of MSA [45]. In patients with drug induced parkinsonism (DIP) unrelated to PD, olfactory function assessed by the cross cultural smell identification test and cardiac 123I-metaiodobenzylguanidine uptake were normal [46]. Urinary symptoms, excessive daytime sleepiness, restless legs syndrome, attention deficit, and hyposmia were associated with PD and may be helpful to differentiate between DIP and PD in the early stages [47]. Essential tremor patients had significant cognitive dysfunction, neuropsychiatric problems including depression and have complained about significant autonomic dysfunction and excessive daytime somnolence compared to normal controls. Patients with ET have several NMS similar to those of patients with PD, which have a similar impact on their quality of life [48].

NMS AND QUALITY OF LIFE

Non-motor symptoms and levodopa-resistant motor symptoms dominate the clinical picture and disability of patients with late stage PD [49]. The scores of Korean version of 39-item Parkinson’s disease questionnaire (PDQ-39), instrument for evaluating healthrelated quality of life (HrQoL) in PD patients, demonstrated significant relationships with NMSS scores [50]. The NMSS scores also significantly correlated with PDQ-39 scores in patients with MSA and PSP [51]. NMS progression contributes importantly to HrQoL decline [52] with a growing emphasis on the importance of HrQoL when managing PD patients.

CONCLUSIONS

Non-motor symptoms in PD have close relationship with motor signs and are now recognized as an integral component of multisystem disorder. NMS often carry a greater impact than motor signs in PD, especially in the late stage of PD. Although many NMS are resistant to levodopa treatment, optimizing dopaminergic therapies is viable avenue to improve control of some disabling NMS in PD. In recognition and treatment of NMS are increasingly emphasized in the care of PD patients.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

References

1. Lang AE, Lozano AM. Parkinson’s disease. First of two parts. N Engl J Med 1998;339:1044–1053.
2. Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol 2000;247 Suppl 2:II3–II10.
3. Chaudhuri KR, Healy DG, Schapira AH, ; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5:235–245.
4. Stacy M. Nonmotor symptoms in Parkinson’s disease. Int J Neurosci 2011;121 Suppl 2:9–17.
5. Lim SY, Lang AE. The nonmotor symptoms of Parkinson’s disease--an overview. Mov Disord 2010;25 Suppl 1:S123–S130.
6. Kim J, Kim M, Kwon do Y, Seo WK, Kim JH, Baik JS, et al. Clinical characteristics of impulse control and repetitive behavior disorders in Parkinson’s disease. J Neurol 2013;260:429–437.
7. Biglan KM, Holloway RG Jr, McDermott MP, Richard IH, ; Parkinson Study Group CALM-PD Investigators . Risk factors for somnolence, edema, and hallucinations in early Parkinson disease. Neurology 2007;69:187–195.
8. Maricle RA, Valentine RJ, Carter J, Nutt JG. Mood response to levodopa infusion in early Parkinson’s disease. Neurology 1998;50:1890–1892.
9. Postuma RB, Aarsland D, Barone P, Burn DJ, Hawkes CH, Oertel W, et al. Identifying prodromal Parkinson’s disease:pre-motor disorders in Parkinson’s disease. Mov Disord 2012;27:617–626.
10. Li H, Zhang M, Chen L, Zhang J, Pei Z, Hu A, et al. Nonmotor symptoms are independently associated with impaired health-related quality of life in Chinese patients with Parkinson’s disease. Mov Disord 2010;25:2740–2746.
11. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson’s disease. J Am Geriatr Soc 2004;52:784–788.
12. Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009;24:1641–1649.
13. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003;18:738–750.
14. Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F, Sethi K, Odin P, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMS-Quest study. Mov Disord 2006;21:916–923.
15. Chaudhuri KR, Martinez-Martin P. Quantitation of nonmotor symptoms in Parkinson’s disease. Eur J Neurol 2008;15 Suppl 2:2–7.
16. Koh SB, Kim JW, Ma HI, Ahn TB, Cho JW, Lee PH, et al. Validation of the Korean-version of the nonmotor symptoms scale for Parkinson’s disease. J Clin Neurol 2012;8:276–283.
17. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197–211.
18. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991;114(Pt 5):2283–2301.
19. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 2012;72:893–901.
20. Martinez-Castrillo JC, Vela L, del Val J, Alonso-Canovas A. Nonmotor disorders and their correlation with dopamine:can they be treated by currently available methods? Neurologist 2011;17(6 Suppl 1):S9–S17.
21. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol 2009;8:464–474.
22. Politis M, Piccini P, Pavese N, Koh SB, Brooks DJ. Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson’s disease: an in vivo 11C-raclopride PET study. Exp Neurol 2008;214:112–116.
23. Loeffler DA, LeWitt PA, Juneau PL, Camp DM, DeMaggio AJ, Havaich MK, et al. Influence of repeated levodopa administration on rabbit striatal serotonin metabolism, and comparison between striatal and CSF alterations. Neurochem Res 1998;23:1521–1525.
24. Burn DJ, Rowan EN, Allan LM, Molloy S, O’Brien JT, McKeith IG. Motor subtype and cognitive decline in Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 2006;77:585–589.
25. Burn DJ, Landau S, Hindle JV, Samuel M, Wilson KC, Hurt CS, et al. Parkinson’s disease motor subtypes and mood. Mov Disord 2012;27:379–386.
26. Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O’Brien JT, Brooks DJ, et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 2013;80:276–281.
27. Storch A, Schneider CB, Wolz M, Stürwald Y, Nebe A, Odin P, et al. Nonmotor fluctuations in Parkinson disease:severity and correlation with motor complications. Neurology 2013;80:800–809.
28. Lyoo CH, Ryu YH, Lee MJ, Lee MS. Striatal dopamine loss and discriminative sensory dysfunction in Parkinson’s disease. Acta Neurol Scand 2012;126:344–349.
29. Lee MS, Lyoo CH, Lee MJ, Sim J, Cho H, Choi YH. Impaired finger dexterity in patients with Parkinson’s disease correlates with discriminative cutaneous sensory dysfunction. Mov Disord 2010;25:2531–2535.
30. Lee JM, Koh SB, Chae SW, Seo WK, Kwon do Y, Kim JH, et al. Postural instability and cognitive dysfunction in early Parkinson’s disease. Can J Neurol Sci 2012;39:473–482.
31. Oka H, Toyoda C, Yogo M, Mochio S. Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease. J Neurol 2010;257:969–976.
32. Goldstein DS, Sewell L, Holmes C. Association of anosmia with autonomic failure in Parkinson disease. Neurology 2010;74:245–251.
33. Pacchetti C, Manni R, Zangaglia R, Mancini F, Marchioni E, Tassorelli C, et al. Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson’s disease. Mov Disord 2005;20:1439–1448.
34. Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. Manifestations of Parkinson disease differ in association with REM sleep behavior disorder. Mov Disord 2008;23:1665–1672.
35. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol 2005;4:605–610.
36. Kim JS, Oh YS, Lee KS, Kim YI, Yang DW, Goldstein DS. Association of cognitive dysfunction with neurocirculatory abnormalities in early Parkinson disease. Neurology 2012;79:1323–1331.
37. Kim SH, Park JH, Kim YH, Koh SB. Stereopsis in drug na- ïve Parkinson’s disease patients. Can J Neurol Sci 2011;38:299–302.
38. Koh SB, Suh SI, Kim SH, Kim JH. Stereopsis and extrastriate cortical atrophy in Parkinson’s disease: a voxel-based morphometric study. Neuroreport 2013;24:229–232.
39. Kwon KY, Kang SH, Kim M, Lee HM, Jang JW, Kim JY, et al. Nonmotor symptoms and cognitive decline in de novo Parkinson’s disease. Can J Neurol Sci 2014;41:597–602.
40. Hawkes C. Olfaction in neurodegenerative disorder. Mov Disord 2003;18:364–372.
41. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Quinn N. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 1995;91:247–250.
42. Müller A, Müngersdorf M, Reichmann H, Strehle G, Hummel T. Olfactory function in Parkinsonian syndromes. J Clin Neurosci 2002;9:521–524.
43. Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ. Olfactory function distinguishes vascular parkinsonism from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75:1749–1752.
44. McKinnon JH, Demaerschalk BM, Caviness JN, Wellik KE, Adler CH, Wingerchuk DM. Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders? Neurologist 2007;13:382–385.
45. Jecmenica-Lukic M, Poewe W, Tolosa E, Wenning GK. Premotor signs and symptoms of multiple system atrophy. Lancet Neurol 2012;11:361–368.
46. Lee PH, Yeo SH, Yong SW, Kim YJ. Odour identification test and its relation to cardiac 123I-metaiodobenzylguanidine in patients with drug induced parkinsonism. J Neurol Neurosurg Psychiatry 2007;78:1250–1252.
47. Kim JS, Youn J, Shin H, Cho JW. Nonmotor symptoms in drug-induced parkinsonism and drug-naïve Parkinson disease. Can J Neurol Sci 2013;40:36–41.
48. Lee SM, Kim M, Lee HM, Kwon KY, Koh SB. Nonmotor symptoms in essential tremor: comparison with Parkinson’s disease and normal control. J Neurol Sci 2015;349:168–173.
49. Coelho M, Ferreira JJ. Late-stage Parkinson disease. Nat Rev Neurol 2012;8:435–442.
50. Kwon DY, Kim JW, Ma HI, Ahn TB, Cho J, Lee PH, et al. Translation and validation of the Korean version of the 39-item Parkinson’s disease questionnaire. J Clin Neurol 2013;9:26–31.
51. Lee CN, Kim M, Lee HM, Jang JW, Lee SM, Kwon DY, et al. The interrelationship between non-motor symptoms in Atypical Parkinsonism. J Neurol Sci 2013;327:15–21.
52. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, ; NMSS Validation Group. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord 2011;26:399–406.

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Table 1.

Non-motor symptoms of Parkinson’s disease and their responsiveness to dopamine therapy [26]

Responsive to DRT Unresponsive to DRT Induced by DRT
Neuropsychiatric symptoms Depression Cognitive dysfunction Hallucination
Apathy Attension deficit Delusion
Anxiety Dementia DDS
Anhedonia Confusion Punding
Off period related panic attacks ICD
Sleep disorders RLS Non-REM sleep related movement disorders EDS
PLM Vivid dreaming
RBD* Insomnia
Sleep-disordered breathing
Autonomic symptoms Urgency (detrusor overactivity) Frequency Orthostatic hypotension
Nocturia Sweating
Erectile dysfunction
Gastrointestinal symptoms Dribbling of saliva* Ageusia
Constipation Dysphagia Nausea
Unsatisfactory voiding of bowel Reflux, vomiting Diarrhea
Fecal incontinence
Sensory symptoms Secondary pain
Primary pain (central pain) Paresthesia
Fluctuation-related pain Olfactory disturbance
Visual dysfunction
Other symptoms Non-motor fluctuations Ankle swelling
Fatigue Blurred vision
*

some anecdotal reports of response to dopaminergic treatment. Some unmarked symptoms might also respond to treatment. DDS: dopamine dysregulation syndrome, DRT: dopamine replacement therapy, EDS: excessive daytime sleepiness, ICD: impulse control disorders, PLM: periodic limb movement, RBD: rapid eyeball movement behavior disorder, REM: rapid eyeball movement, RLS: restless legs syndrome.