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Non-motor symptoms in Parkinson's disease
Parkinsonism and Related Disorders xxx (2015) 1e4
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Non-motor symptoms in Parkinson's disease Ronald F. Pfeiffer Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 September 2015 Accepted 2 September 2015
With the growing awareness of the presence of non-motor symptoms in Parkinson's disease (PD) has come the realization that these non-motor features play a tremendously important, and sometimes dominant, role in the management and even the diagnosis of the disorder. Despite this, a reluctance to formally address and treat the non-motor symptoms of PD remains and quality of life for PD patients suffers. This review provides an overview of the impact non-motor symptoms have on persons with PD, along with a brief description of some of the more common non-motor features of PD. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Nonmotor dysfunction
1. Introduction Over the past several decades much has been written about the “discovery” of non-motor dysfunction as a part of Parkinson's disease (PD). What often is not recognized is that in this instance the term “discovery” is actually a misnomer, because many of these aspects of PD were already recognized and described by none other than James Parkinson himself in his classic treatise on the disorder that now bears his name. Sleep disturbances, gastrointestinal dysfunction, bladder dysfunction, and even fatigue (extreme exhaustion) all are described by Dr. Parkinson. What has changed is the growing recognition of the prevalence and importance of nonmotor dysfunction in both the diagnosis and management of PD. It is now widely accepted that PD is characterized not only by its motor aspects, but also by numerous non-motor symptoms (NMS) that encompass sensory abnormalities, behavioral changes, sleep disturbances, autonomic dysfunction, and some more difficult to categorize symptoms such as fatigue. NMS are by all accounts very common in individuals with PD. In two recent studies, at least one NMS was reported by almost 100% of patients [1,2] and in yet another, NMS were present in 100% of PD subjects who were also experiencing motor fluctuations [3]. NMS also occur frequently in individuals without PD as a part of normal aging e studies suggest 68e88% of normal, comparably aged individuals will experience at least one NMS; this should impart caution in rushing to attribute all NMS described by PD patients to their PD [1,2]. However, individuals with PD tend to have a larger number of different NMS, compared with normal controls (mean
E-mail address: [email protected].
8.4 vs. 2.8 in one study), and the NMS in persons with PD tend to be more frequent and more severe [2,4]. NMS also may be the presenting clinical feature of PD in over 20% of individuals [5]. In such situations, PD diagnosis often is delayed and individuals are subjected to a variety of specialist referrals and inappropriate treatments [5]. Most prominently, pain is likely to be attributed to orthopedic or rheumatologic causes, and it is not uncommon for individuals eventually diagnosed with PD to have been treated with a variety of pain and anti-inflammatory medications and even to have received steroid injections for suspected bursitis and other diagnoses. Some NMS may actually appear years, and even decades, before the classic motor features of PD make their appearance. As with parkinsonian motor abnormalities, NMS also may show a pattern of fluctuation [3,6]. Non-motor fluctuations tend to correlate with the motor fluctuations and tend to emerge during motor “off” periods; this is especially true of behavioral NMS [6]. For other NMS, this pattern is less robust, but it is rare for individuals to experience non-motor fluctuations exclusively [3,6]. For a significant percentage of individuals e 28% in one study - their non-motor fluctuations cause a greater degree of disability than their motor fluctuations [3]. This somewhat surprising fact has been reinforced by more recent studies that have demonstrated that NMS have a greater impact on health-related quality of life than do motor abnormalities, even early in the course of PD. Other studies have documented that NMS, specifically hallucinations, are the strongest predictor of nursing home placement for persons with PD. In the nursing home setting, NMS appear to be virtually universally present in patients with PD; individuals typically display multiple types of NMS, which occur with great frequency [7]. In persons with PD living at home,
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Please cite this article in press as: R.F. Pfeiffer, Non-motor symptoms in Parkinson's disease, Parkinsonism and Related Disorders (2015), http:// dx.doi.org/10.1016/j.parkreldis.2015.09.004
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R.F. Pfeiffer / Parkinsonism and Related Disorders xxx (2015) 1e4
NMS in the form of neuropsychiatric symptoms also are important determinants of caregiver burden. In light of the importance and impact that NMS hold for persons with PD and for their family, it is vitally important that physicians caring for them are familiar with and are attentive to diagnosing NMS when they occur. This can be difficult because patients themselves may not mention them to their physicians, either because they do not associate them with PD or, in some instances, out of embarrassment. Thus, it falls on the physician to query patients regarding NMS. Questionnaires have been developed to assist with this. Although recognition of NMS by physicians- neurologists and non-neurologists alike- has improved with the cornucopia of published reports that have been published on NMS in PD in recent years, prompt diagnosis still lags and assuring appropriate treatment looms as a potentially greater hurdle. In one recent report, specific treatment of NMS was found to be distressingly infrequent in routine clinical care of PD patients e only 28% of those with moderate to severe depression were being prescribed pharmacologic treatment, and only 2% of patients who screened positive for REM sleep behavior disorder, 13% of persons with significant urinary symptoms, 3% of men with erectile dysfunction, and 66% of individuals with moderate or greater constipation were receiving treatment for their NMS [8]. So, exactly what are the NMS of PD? Other presentations/contributions at this Congress and in these Proceedings will address individual manifestations in more detail, so just a brief summary will be delineated here and treatment issues will be mentioned only in passing. 2. Abnormalities of sensation A variety of abnormalities of sensation have been described in the setting of PD. Impairment of olfaction is perhaps the most widely recognized, but a variety of problems with vision and patterns of pain are also prone to occur. Olfactory impairment is present in up to 90% of persons with PD, often already at the time of diagnosis. However, over 70% of affected individuals may be unaware that their sense of smell is impaired [9]. Although some investigators report that impaired olfaction is independent of disease stage and duration [9], others report that olfactory impairment is associated with higher disease severity and faster progression and that severe hyposmia in PD patients may predict the development of PD dementia [10]. Olfactory testing has been suggested to be useful for screening for PD but can be timeconsuming in the clinical setting. Of interest, in this regard, is the recent report that testing with only three odors (coffee, peppermint, anise) provided comparable results to testing with the entire odor panel [11]. Both same-day and longer term improvement in odor identification has been reported with olfactory training, but confirmation with additional studies is necessary [12]. In the clinic, it is very common for patients with PD to voice their frustration with vision problems and their frustration often is amplified by prior visits to their ophthalmologist in which they have been informed that no explanation for their visual symptoms can be found. However, with more detailed testing, a variety of abnormalities potentially affecting vision emerge in the setting of PD, including reduced contrast sensitivity, impaired color discrimination, convergence insufficiency, and dry eye syndrome; as a group, PD patients also have reduced distance and near best corrected visual acuity, compared with controls [13]. Abnormalities affecting structures around the eye, such as seborrheic blepharitis and meibomian gland disease also are more common in individuals with PD [13]. Stereopsis also is disturbed in PD. The basis for visual symptoms in PD may be multifactorial, but elegant work has demonstrated that thinning of the retinal nerve fiber layer and the
inner retinal fovea are characteristic of PD and deposition of alphasynuclein has been described in amacrine and ganglion cells within the inner retina [14]. In a recent report, pain was noted to be present in 76% of 100 individuals with PD [15]. Pain in PD has been classified into five categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, primary or central parkinsonian pain, and akathitic discomfort. Of these, musculoskeletal pain is the most frequent, described in almost 50% of individuals experiencing pain, although this is also the category in which it likely is most difficult to separate pain directly related to PD from pain due to other causes. An alternative approach to classifying pain in PD divides pain into primary PD pain (e.g. pain related to dyskinesia, “off” period dystonia, central pain) and secondary PD pain (e.g. musculoskeletal pain, orofacial pain, limb and abdominal pain). Not surprisingly, pain can severely impact quality of life for individuals experiencing it. Management approaches to pain in the setting of PD depend upon the cause of the pain and may include oral pharmacological approaches, botulinum toxin injections, physical therapy, and pain management and other specialist consultations.
3. Behavioral changes Depression is common in PD; one review and meta-analysis reported a prevalence of major depressive disorder in 17%, minor depression in 22% and dysthymia in 13% of individuals with PD [16]. Depression may occur at any time during the course of PD. It may precede the appearance of motor dysfunction and may be an early prodromal sign of PD. It often is attributed to serotonin deficiency, but a recent study documented reduced serotonin raphe transporter availability to correlate with tremor but not depression in individuals with PD [17]. Persons who develop depression early in the course of PD have an increased risk of greater impairment of motor function and increased disability over time. Antidepressant medications have been shown to be effective in treating parkinsonian depression; evidence of benefit of transcranial magnetic stimulation is also surfacing. The reported prevalence of anxiety in PD is 25e40% [18]. Like depression, anxiety may appear at any time during the course of PD. It also may precede the appearance of the classic motor features of PD and persons with anxiety have an increased risk of developing PD. In PD anxiety most often takes the form of generalized anxiety disorder, panic disorder, or one of the phobic disorders. It may become quite strikingly evident as a wearing off phenomenon. A recent meta-analysis suggests that the prevalence of apathy in PD is approximately 40% [19]. It can be difficult to separate apathy from depression and fatigue in PD patients, but what distinguishes apathy is the indifference of the affected person, which is especially frustrating for caregivers. An association between apathy and executive dysfunction, specifically difficulty with initiation, is apparent in PD [20]. Perhaps the complication, whether motor or non-motor, most feared by patients with PD and their family members is the development of dementia. Unfortunately, it is a complication that is eventually realized in over 80% of individuals with PD who survive for 20 years [21]. Although cognitive difficulties clearly become more frequent and prominent as PD progresses, mild cognitive impairment may already be present in almost 25% of PD patients in the early stages of the disorder [22]. The diagnostic division between PD dementia and dementia with Lewy bodies has been drawn rather arbitrarily, but the actual distinction can be more indistinct. Current treatment of cognitive impairment in PD is centered on cholinesterase inhibitors, but is suboptimal.
Please cite this article in press as: R.F. Pfeiffer, Non-motor symptoms in Parkinson's disease, Parkinsonism and Related Disorders (2015), http:// dx.doi.org/10.1016/j.parkreldis.2015.09.004
R.F. Pfeiffer / Parkinsonism and Related Disorders xxx (2015) 1e4
4. Autonomic dysfunction Autonomic dysfunction in PD is common and virtually all aspects of autonomic function may be affected. Autonomic dysfunction may occur at any stage of PD, and some facets, such as constipation, may become evident years or even decades before the emergence of motor dysfunction. Orthostatic hypotension is the most widely recognized aspect of cardiovascular dysfunction in PD. It may be present in almost 60% of persons with PD, although only a minority of these patients may be symptomatic. The diagnosis of symptomatic orthostatic hypotension in PD can be difficult. Not all patients will experience the classic symptom of lightheadedness upon standing, but instead may describe symptoms such as blurred vision or foggy thinking upon standing, “coathanger” headache or pain in the lower back or buttocks regions upon standing, or just lethargy when up and about. In others, the traditional manner of obtaining orthostatic blood pressure measurements in the clinic may not produce an unequivocal drop in blood pressure and other approaches, such as tilt-table testing, 24-h ambulatory blood pressure monitoring, or use of continuous non-invasive arterial pressure monitors might be needed [23]. Additional blood pressure-related problems that PD patients may experience, and which may require innovative management, include nocturnal hypertension and post-prandial hypotension. Gastrointestinal dysfunction in PD may appear in a variety of guises, including dysphagia, gastroparesis, small intestinal bacterial overgrowth, and bowel dysfunction with both decreased frequency and difficulty with the act of defecation itself [24]. Less frequent and inefficient swallowing may lead to drooling but also may be responsible for more dangerous complications such as aspiration. Although it has not been studied as extensively as some other aspects of gastrointestinal dysfunction in PD, impaired gastric emptying can be an important source of not only clinical distress but also pharmacologic misadventure. PD patients with gastroparesis may experience early satiety, reduced appetite, bloating, abdominal distension, nausea, vomiting, and progressive weight loss. Impaired gastric emptying also may impair effective levodopa absorption, since levodopa must reach the small intestine in order to be absorbed. Small intestinal function has been studied even less than gastroparesis in PD, but accumulating evidence suggests that it also may be impaired in PD. Small intestinal bacterial overgrowth has been described in patients with PD and may be responsible for the development of motor fluctuations in some [24]. Bowel dysfunction in PD may take two forms, decreased bowel movement frequency and difficulty with the act of defecation itself. Decreased bowel movement frequency is the result of slowed colonic transit of fecal material, whereas defecatory dysfunction is due to failure of the anal sphincter and puborectalis muscles to relax appropriately to facilitate emptying of the rectal contents [24]. Although the reported frequency of urinary symptoms in persons with PD varies considerably between studies, all agree that urinary symptoms are common and more recent studies indicate that the prevalence of lower urinary tract symptoms may be in the range of 25e50% [25]. Urodynamic studies document abnormalities in a much higher percentage of PD patients [26]. Detrusor overactivity is the most frequent urodynamic abnormality, producing urinary urgency, frequency, nocturia, and incontinence of the urge type [26]. However, detrusor hypocontractility and sphincter relaxation problems may also occur [26]. Although urinary symptoms become more frequent as PD progresses, urinary dysfunction also may develop early in the course of PD. A broad array of antimuscarinic anticholinergic drugs are available to treat overactive bladder dysfunction and newer approaches, such as beta-3adrenergic agonists and intravesicular injection of botulinum
3
toxin, are also available. However, treatment of underactive bladder is more limited and self-catheterization may be necessary. Sexual dysfunction is very common in both men and women with PD, but studies addressing this distressing aspect of autonomic function in PD are sparse. Sexual satisfaction is lower in men with PD than in women, possibly related to performance problems due to erectile dysfunction with consequent lowered self-esteem [27]. Sexual dysfunction in men with PD typically takes the form of erectile dysfunction, difficulty reaching orgasm, or premature ejaculation; in women it most often involves low sexual desire, difficulty with arousal, and difficulty with orgasm. The development of erectile dysfunction may precede the appearance of motor dysfunction. Testosterone deficiency has been identified in some men with PD experiencing sexual dysfunction. Thermoregulatory dysfunction in PD has received even less attention than sexual dysfunction. Paroxysmal drenching sweats are reported by a number of people with PD. Sweating problems may be more likely to occur in PD patients experiencing motor fluctuations, but sweating episodes also can appear independent of motor status. This type of episodic hyperhidrosis can be tremendously embarrassing for individuals experiencing it and can significantly impact their quality of life. No effective pharmacologic treatment for the drenching sweats has been reported, but improvement after deep brain stimulation surgery has been described [28]. 5. Sleep disturbances Disturbed or impaired sleep is very common in the setting of PD and its prevalence may reach close to 90% [29]. The most common form of insomnia in PD is sleep fragmentation, with frequent nocturnal awakenings. The basis for sleep fragmentation in PD is multifactorial and may include impaired “turnability” due to nighttime rigidity and bradykinesia, nocturia, medication effects, periodic limb movements, and others. Effective treatment of sleep fragmentation is dependent upon identifying and then targeting the suspected source of the problem. REM sleep behavior disorder (RBD), characterized by continued ability to move during REM sleep, has gained considerable attention in recent years, both as a manifestation of PD and as a risk factor for the development of PD. The prevalence of RBD in PD isn't known with certainty, but may be in the range of 25e50%. RBD may be present years before the classic motor features of PD emerge. In fact, some studies suggest that individuals with RBD have an approximate 80e90% risk of eventually developing PD. It is important to identify PD patients with RBD because it is potentially dangerous, both to the patient and to the patient's bed partner, and effective treatment exists. 6. Fatigue The feeling of tiredness or exhaustion that characterizes fatigue has been increasingly recognized in the setting of PD. Fatigue often is identified by persons with PD as one of their most disabling symptoms with the greatest impact on their quality of life [30]. Little is known of the mechanism of fatigue in PD and effective treatment of fatigue in PD is lacking. 7. Summary NMS are now recognized as extremely frequent and important components of PD that can appear during all stages of the disorder, including the premotor stage. Beyond their importance in facilitating the diagnosis of PD, the fact that many NMS may respond to appropriate treatment makes it vital that neurologists are familiar
Please cite this article in press as: R.F. Pfeiffer, Non-motor symptoms in Parkinson's disease, Parkinsonism and Related Disorders (2015), http:// dx.doi.org/10.1016/j.parkreldis.2015.09.004
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with the NMS of PD and that they seek their presence by asking patients about them and, if present, that they then either initiate appropriate treatment or make appropriate referral for treatment of the NMS. The tendency to assume that someone else will manage these problems needs to be guarded against. Financial disclosures 2013e2015 Employment, Stock Ownership, Intellectual Property Rights Nothing to Disclose Royalties (for books edited) CRC Press (Taylor & Francis); Humana Press (Springer) Journal Editor Parkinsonism & Related Disorders Honoraria (for lectures) Teva, UCB, USWorldMeds Honoraria (for consulting) Pfizer, Chelsea, Acadia, Lundbeck, Clintara/Acorda Research Grants, Contracts None Legal Consulting Tucker Ellis & West; Thomas Thomas & Hafer References [1] H.-S. Kim, S.-M. Cheon, J.-W. Seo, H.-J. Ryu, K.-W. Park, J.W. Kim, Nonmotor symptoms more closely related to Parkinson's disease: comparison with normal elderly, J. Neurol. Sci. 324 (2013) 70e73. [2] S. Krishnan, G. Sarma, S. Sarma, A. Kishore, Do nonmotor symptoms in Parkinson's disease differ from normal aging? Mov. Disord. 26 (2011) 2110e2113. [3] T. Witjas, E. Kaphan, J.P. Azulay, O. Blin, M. Ceccaldi, J. Pouget, et al., Nonmotor fluctuations in Parkinson's disease: frequent and disabling, Neurology 59 (2002) 408e413. [4] T.K. Khoo, A.J. Yarnall, G.W. Duncan, S. Coleman, J.T. O'Brien, D.J. Brooks, et al., The spectrum of nonmotor symptoms in early Parkinson disease, Neurology 80 (2013) 276e281. [5] S.S. O'Sullivan, D.R. Williams, D.A. Gallagher, L.A. Massey, L. Silveira-Moriyama, A.J. Lees, Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study, Mov. Disord. 23 (2008) 101e106. [6] A. Storch, C.B. Schneider, M. Wolz, Y. Stürwald, A. Nebe, P. Odin, et al., Nonmotor fluctuations in Parkinson disease, Neurology 80 (2013) 800e809. [7] N.J. Weerkamp, G. Tissingh, P.J. Poels, S.U. Zuidema, M. Munneke, R.T. Koopmans, et al., Nonmotor symptoms in nursing home residents with Parkinson's disease: prevalence and effect on quality of life, J. Am. Geriatr. Soc. 61 (2013) 1714e1721. [8] F. Baig, M. Lawton, M. Rolinski, C. Ruffmann, K. Nithi, S.G. Evetts, et al., Delineating nonmotor symptoms in early Parkinson's disease and first-degree relatives, Mov. Disord. (2015) (epub ahead of print). [9] R.L. Doty, D.A. Deems, S. Stellar, Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease
duration, Neurology 38 (1988) 1237e1244. [10] S. Cavaco, A. Goncalves, A. Mendes, N. Vila-Ch~ a, I. Moreira, J. Fernandes, et al., Abnormal olfaction in Parkinson disease is related to faster disease progression, Behav. Neurol. 2015 (2015) 976589. [11] S. Casjens, A. Eckert, D. Woitalla, G. Ellrichmann, M. Turewicz, C. Stephan, et al., Diagnostic value of the impairment of olfaction in Parkinson's disease, PLoS One 8 (2013) e64735. [12] K. Knudsen, M. Flensborg Damholdt, K. Mouridsen, P. Borghammer, Olfactory function in Parkinson's disease e effects of training, Acta Neurol. Scand. (2015) (epub ahead of print). ski, K. Honczarenko, A. Potemkowski, K. Safranow, [13] B. Nowacka, W. Lubin Ophthalmological features of Parkinson disease, Med. Sci. Monit. 20 (2014) 2243e2249. [14] I. Bodis-Wollner, P.B. Kozlowski, S. Glazman, S. Miri, a-Synuclein in the inner retina in Parkinson disease, Ann. Neurol. 75 (2014) 964e966. [15] P. Valkovic, M. Minar, H. Singliarova, J. Harsany, M. Hanakova, J. Martinkova, et al., Pain in Parkinson's disease: a cross-sectional study of its prevalence, types, and relationship to depression and quality of life, PLoS One 10 (2015) e0136541. [16] J.S. Riejnders, U. Ehrt, W.E. Weber, D. Aarsland, A.F. Leentjens, A systematic review of prevalence studies of depression in Parkinson's disease, Mov. Disord. 23 (2008) 183e189. [17] Z. Qamhawi, D. Towey, B. Shah, G. Pagano, J. Seibyl, K. Marek, et al., Clinical correlates of raphe serotonergic dysfunction in early Parkinson's disease, Brain (2015) (epub ahead of print). [18] T. Simuni, H.H. Fernandez, Anxiety in Parkinson's disease, in: R.F. Pfeiffer, I. Bodis-Wollner (Eds.), Parkinson's Disease and Nonmotor Dysfunction, second ed., Humana Press, New York, 2013, pp. 17e29. [19] M.G. Den Brock, J.W. van Dalen, W.A. van Gool, E.P. Moll van Charante, R.M. de Bie, E. Richard, Apathy in Parkinson's disease: a systematic review and metaanalysis, Mov. Disord. 30 (2015) 759e769. [20] A. Meyer, R. Zimmermann, U. Gschwandtner, F. Hatz, H. Bousleiman, N. Schwarz, et al., Apathy in Parkinson's disease is related to executive function, gender and age but not to depression, Front. Aging Neurosci. 6 (2015) 350, http://dx.doi.org/10.3389/fnagi.2014.00350. [21] M.A. Hely, W.G. Reid, M.A. Adena, G.M. Halliday, J.G. Morris, The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years, Mov. Disord. 23 (2008) 837e844. [22] E. Stefanova, L. Ziropadja, T. Stojkovi c, I. Stankovi c, A. Tomi c, M. Je^ cmenicaLuki c, et al., Mild cognitive impairment in early Parkinson's disease using the movement disorder society task force criteria: cross-sectional study in Hoehn and Yahr stage 1, Dement. Geriatr. Cogn. Disord. 40 (2015) 199e209. [23] A.M. Hellman, S.P. Shah, S.M. Pawlowski, J.E. Duda, J.F. Morley, Continuous non-invasive monitoring to detect covert autonomic dysfunction in Parkinson's disease, Parkinsonism Relat. Disord. 21 (2015) 723e728. [24] A. Fasano, N.P. Visanji, L.W. Liu, A.E. Lang, R.F. Pfeiffer, Gastrointestinal dysfunction in Parkinson's disease, Lancet Neurol. 14 (2015) 625e639. [25] K. Winge, Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders, Handb. Clin. Neurol. 130 (2015) 335e356. [26] R. Sakakibara, J. Panicker, E. Finazzi-Agro, V. Iacovelli, H. Bruschini, The Parkinson’s Disease Subcommittee, The Neurourology Promotion Committee in the International Continence Society, A guideline for the management of bladder dysfunction in Parkinson's disease and other gait disorders, Neurourol. Urodyn. (2015) (epub ahead of print). [27] G. Bronner, O.S. Cohen, G. Yahalom, E. Kozlova, Y. Orlev, N. Molshatzki, et al., Correlates of quality of sexual life in male and female patients with Parkinson disease and their partners, Parkinsonism Relat. Disord. 20 (2014) 1085e1088. [28] E. Trachani, C. Constantoyannis, V. Sirrou, Z. Kefalopoulou, E. Markaki, E. Chroni, Effects of subthalamic nucleus deep brain stimulation on sweating function in Parkinson's disease, Clin. Neurol. Neurosurg. 112 (2010) 213e217. [29] M.M. Kurtis, C. Rodriguez-Blazquez, P. Martinez-Martin, ELEP Group. Relationship between sleep disorders and other non-motor symptoms in Parkinson's disease, Parkinsonism Relat. Disord. 19 (2013) 1152e1155. [30] V.B. Dogan, A. Koksal, A. Dirican, S. Baybas, A. Dirican, G.B. Dogan, Independent effect of fatigue on health-related quality of life in patients with idiopathic Parkinson's disease, Neurol. Sci. (2015) (epub ahead of print).
Please cite this article in press as: R.F. Pfeiffer, Non-motor symptoms in Parkinson's disease, Parkinsonism and Related Disorders (2015), http:// dx.doi.org/10.1016/j.parkreldis.2015.09.004
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Non-motor symptoms in Parkinson's disease Ronald F. Pfeiffer Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 September 2015 Accepted 2 September 2015
With the growing awareness of the presence of non-motor symptoms in Parkinson's disease (PD) has come the realization that these non-motor features play a tremendously important, and sometimes dominant, role in the management and even the diagnosis of the disorder. Despite this, a reluctance to formally address and treat the non-motor symptoms of PD remains and quality of life for PD patients suffers. This review provides an overview of the impact non-motor symptoms have on persons with PD, along with a brief description of some of the more common non-motor features of PD. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Parkinson's disease Nonmotor dysfunction
1. Introduction Over the past several decades much has been written about the “discovery” of non-motor dysfunction as a part of Parkinson's disease (PD). What often is not recognized is that in this instance the term “discovery” is actually a misnomer, because many of these aspects of PD were already recognized and described by none other than James Parkinson himself in his classic treatise on the disorder that now bears his name. Sleep disturbances, gastrointestinal dysfunction, bladder dysfunction, and even fatigue (extreme exhaustion) all are described by Dr. Parkinson. What has changed is the growing recognition of the prevalence and importance of nonmotor dysfunction in both the diagnosis and management of PD. It is now widely accepted that PD is characterized not only by its motor aspects, but also by numerous non-motor symptoms (NMS) that encompass sensory abnormalities, behavioral changes, sleep disturbances, autonomic dysfunction, and some more difficult to categorize symptoms such as fatigue. NMS are by all accounts very common in individuals with PD. In two recent studies, at least one NMS was reported by almost 100% of patients [1,2] and in yet another, NMS were present in 100% of PD subjects who were also experiencing motor fluctuations [3]. NMS also occur frequently in individuals without PD as a part of normal aging e studies suggest 68e88% of normal, comparably aged individuals will experience at least one NMS; this should impart caution in rushing to attribute all NMS described by PD patients to their PD [1,2]. However, individuals with PD tend to have a larger number of different NMS, compared with normal controls (mean
E-mail address: [email protected].
8.4 vs. 2.8 in one study), and the NMS in persons with PD tend to be more frequent and more severe [2,4]. NMS also may be the presenting clinical feature of PD in over 20% of individuals [5]. In such situations, PD diagnosis often is delayed and individuals are subjected to a variety of specialist referrals and inappropriate treatments [5]. Most prominently, pain is likely to be attributed to orthopedic or rheumatologic causes, and it is not uncommon for individuals eventually diagnosed with PD to have been treated with a variety of pain and anti-inflammatory medications and even to have received steroid injections for suspected bursitis and other diagnoses. Some NMS may actually appear years, and even decades, before the classic motor features of PD make their appearance. As with parkinsonian motor abnormalities, NMS also may show a pattern of fluctuation [3,6]. Non-motor fluctuations tend to correlate with the motor fluctuations and tend to emerge during motor “off” periods; this is especially true of behavioral NMS [6]. For other NMS, this pattern is less robust, but it is rare for individuals to experience non-motor fluctuations exclusively [3,6]. For a significant percentage of individuals e 28% in one study - their non-motor fluctuations cause a greater degree of disability than their motor fluctuations [3]. This somewhat surprising fact has been reinforced by more recent studies that have demonstrated that NMS have a greater impact on health-related quality of life than do motor abnormalities, even early in the course of PD. Other studies have documented that NMS, specifically hallucinations, are the strongest predictor of nursing home placement for persons with PD. In the nursing home setting, NMS appear to be virtually universally present in patients with PD; individuals typically display multiple types of NMS, which occur with great frequency [7]. In persons with PD living at home,
http://dx.doi.org/10.1016/j.parkreldis.2015.09.004 1353-8020/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: R.F. Pfeiffer, Non-motor symptoms in Parkinson's disease, Parkinsonism and Related Disorders (2015), http:// dx.doi.org/10.1016/j.parkreldis.2015.09.004
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NMS in the form of neuropsychiatric symptoms also are important determinants of caregiver burden. In light of the importance and impact that NMS hold for persons with PD and for their family, it is vitally important that physicians caring for them are familiar with and are attentive to diagnosing NMS when they occur. This can be difficult because patients themselves may not mention them to their physicians, either because they do not associate them with PD or, in some instances, out of embarrassment. Thus, it falls on the physician to query patients regarding NMS. Questionnaires have been developed to assist with this. Although recognition of NMS by physicians- neurologists and non-neurologists alike- has improved with the cornucopia of published reports that have been published on NMS in PD in recent years, prompt diagnosis still lags and assuring appropriate treatment looms as a potentially greater hurdle. In one recent report, specific treatment of NMS was found to be distressingly infrequent in routine clinical care of PD patients e only 28% of those with moderate to severe depression were being prescribed pharmacologic treatment, and only 2% of patients who screened positive for REM sleep behavior disorder, 13% of persons with significant urinary symptoms, 3% of men with erectile dysfunction, and 66% of individuals with moderate or greater constipation were receiving treatment for their NMS [8]. So, exactly what are the NMS of PD? Other presentations/contributions at this Congress and in these Proceedings will address individual manifestations in more detail, so just a brief summary will be delineated here and treatment issues will be mentioned only in passing. 2. Abnormalities of sensation A variety of abnormalities of sensation have been described in the setting of PD. Impairment of olfaction is perhaps the most widely recognized, but a variety of problems with vision and patterns of pain are also prone to occur. Olfactory impairment is present in up to 90% of persons with PD, often already at the time of diagnosis. However, over 70% of affected individuals may be unaware that their sense of smell is impaired [9]. Although some investigators report that impaired olfaction is independent of disease stage and duration [9], others report that olfactory impairment is associated with higher disease severity and faster progression and that severe hyposmia in PD patients may predict the development of PD dementia [10]. Olfactory testing has been suggested to be useful for screening for PD but can be timeconsuming in the clinical setting. Of interest, in this regard, is the recent report that testing with only three odors (coffee, peppermint, anise) provided comparable results to testing with the entire odor panel [11]. Both same-day and longer term improvement in odor identification has been reported with olfactory training, but confirmation with additional studies is necessary [12]. In the clinic, it is very common for patients with PD to voice their frustration with vision problems and their frustration often is amplified by prior visits to their ophthalmologist in which they have been informed that no explanation for their visual symptoms can be found. However, with more detailed testing, a variety of abnormalities potentially affecting vision emerge in the setting of PD, including reduced contrast sensitivity, impaired color discrimination, convergence insufficiency, and dry eye syndrome; as a group, PD patients also have reduced distance and near best corrected visual acuity, compared with controls [13]. Abnormalities affecting structures around the eye, such as seborrheic blepharitis and meibomian gland disease also are more common in individuals with PD [13]. Stereopsis also is disturbed in PD. The basis for visual symptoms in PD may be multifactorial, but elegant work has demonstrated that thinning of the retinal nerve fiber layer and the
inner retinal fovea are characteristic of PD and deposition of alphasynuclein has been described in amacrine and ganglion cells within the inner retina [14]. In a recent report, pain was noted to be present in 76% of 100 individuals with PD [15]. Pain in PD has been classified into five categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, primary or central parkinsonian pain, and akathitic discomfort. Of these, musculoskeletal pain is the most frequent, described in almost 50% of individuals experiencing pain, although this is also the category in which it likely is most difficult to separate pain directly related to PD from pain due to other causes. An alternative approach to classifying pain in PD divides pain into primary PD pain (e.g. pain related to dyskinesia, “off” period dystonia, central pain) and secondary PD pain (e.g. musculoskeletal pain, orofacial pain, limb and abdominal pain). Not surprisingly, pain can severely impact quality of life for individuals experiencing it. Management approaches to pain in the setting of PD depend upon the cause of the pain and may include oral pharmacological approaches, botulinum toxin injections, physical therapy, and pain management and other specialist consultations.
3. Behavioral changes Depression is common in PD; one review and meta-analysis reported a prevalence of major depressive disorder in 17%, minor depression in 22% and dysthymia in 13% of individuals with PD [16]. Depression may occur at any time during the course of PD. It may precede the appearance of motor dysfunction and may be an early prodromal sign of PD. It often is attributed to serotonin deficiency, but a recent study documented reduced serotonin raphe transporter availability to correlate with tremor but not depression in individuals with PD [17]. Persons who develop depression early in the course of PD have an increased risk of greater impairment of motor function and increased disability over time. Antidepressant medications have been shown to be effective in treating parkinsonian depression; evidence of benefit of transcranial magnetic stimulation is also surfacing. The reported prevalence of anxiety in PD is 25e40% [18]. Like depression, anxiety may appear at any time during the course of PD. It also may precede the appearance of the classic motor features of PD and persons with anxiety have an increased risk of developing PD. In PD anxiety most often takes the form of generalized anxiety disorder, panic disorder, or one of the phobic disorders. It may become quite strikingly evident as a wearing off phenomenon. A recent meta-analysis suggests that the prevalence of apathy in PD is approximately 40% [19]. It can be difficult to separate apathy from depression and fatigue in PD patients, but what distinguishes apathy is the indifference of the affected person, which is especially frustrating for caregivers. An association between apathy and executive dysfunction, specifically difficulty with initiation, is apparent in PD [20]. Perhaps the complication, whether motor or non-motor, most feared by patients with PD and their family members is the development of dementia. Unfortunately, it is a complication that is eventually realized in over 80% of individuals with PD who survive for 20 years [21]. Although cognitive difficulties clearly become more frequent and prominent as PD progresses, mild cognitive impairment may already be present in almost 25% of PD patients in the early stages of the disorder [22]. The diagnostic division between PD dementia and dementia with Lewy bodies has been drawn rather arbitrarily, but the actual distinction can be more indistinct. Current treatment of cognitive impairment in PD is centered on cholinesterase inhibitors, but is suboptimal.
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4. Autonomic dysfunction Autonomic dysfunction in PD is common and virtually all aspects of autonomic function may be affected. Autonomic dysfunction may occur at any stage of PD, and some facets, such as constipation, may become evident years or even decades before the emergence of motor dysfunction. Orthostatic hypotension is the most widely recognized aspect of cardiovascular dysfunction in PD. It may be present in almost 60% of persons with PD, although only a minority of these patients may be symptomatic. The diagnosis of symptomatic orthostatic hypotension in PD can be difficult. Not all patients will experience the classic symptom of lightheadedness upon standing, but instead may describe symptoms such as blurred vision or foggy thinking upon standing, “coathanger” headache or pain in the lower back or buttocks regions upon standing, or just lethargy when up and about. In others, the traditional manner of obtaining orthostatic blood pressure measurements in the clinic may not produce an unequivocal drop in blood pressure and other approaches, such as tilt-table testing, 24-h ambulatory blood pressure monitoring, or use of continuous non-invasive arterial pressure monitors might be needed [23]. Additional blood pressure-related problems that PD patients may experience, and which may require innovative management, include nocturnal hypertension and post-prandial hypotension. Gastrointestinal dysfunction in PD may appear in a variety of guises, including dysphagia, gastroparesis, small intestinal bacterial overgrowth, and bowel dysfunction with both decreased frequency and difficulty with the act of defecation itself [24]. Less frequent and inefficient swallowing may lead to drooling but also may be responsible for more dangerous complications such as aspiration. Although it has not been studied as extensively as some other aspects of gastrointestinal dysfunction in PD, impaired gastric emptying can be an important source of not only clinical distress but also pharmacologic misadventure. PD patients with gastroparesis may experience early satiety, reduced appetite, bloating, abdominal distension, nausea, vomiting, and progressive weight loss. Impaired gastric emptying also may impair effective levodopa absorption, since levodopa must reach the small intestine in order to be absorbed. Small intestinal function has been studied even less than gastroparesis in PD, but accumulating evidence suggests that it also may be impaired in PD. Small intestinal bacterial overgrowth has been described in patients with PD and may be responsible for the development of motor fluctuations in some [24]. Bowel dysfunction in PD may take two forms, decreased bowel movement frequency and difficulty with the act of defecation itself. Decreased bowel movement frequency is the result of slowed colonic transit of fecal material, whereas defecatory dysfunction is due to failure of the anal sphincter and puborectalis muscles to relax appropriately to facilitate emptying of the rectal contents [24]. Although the reported frequency of urinary symptoms in persons with PD varies considerably between studies, all agree that urinary symptoms are common and more recent studies indicate that the prevalence of lower urinary tract symptoms may be in the range of 25e50% [25]. Urodynamic studies document abnormalities in a much higher percentage of PD patients [26]. Detrusor overactivity is the most frequent urodynamic abnormality, producing urinary urgency, frequency, nocturia, and incontinence of the urge type [26]. However, detrusor hypocontractility and sphincter relaxation problems may also occur [26]. Although urinary symptoms become more frequent as PD progresses, urinary dysfunction also may develop early in the course of PD. A broad array of antimuscarinic anticholinergic drugs are available to treat overactive bladder dysfunction and newer approaches, such as beta-3adrenergic agonists and intravesicular injection of botulinum
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toxin, are also available. However, treatment of underactive bladder is more limited and self-catheterization may be necessary. Sexual dysfunction is very common in both men and women with PD, but studies addressing this distressing aspect of autonomic function in PD are sparse. Sexual satisfaction is lower in men with PD than in women, possibly related to performance problems due to erectile dysfunction with consequent lowered self-esteem [27]. Sexual dysfunction in men with PD typically takes the form of erectile dysfunction, difficulty reaching orgasm, or premature ejaculation; in women it most often involves low sexual desire, difficulty with arousal, and difficulty with orgasm. The development of erectile dysfunction may precede the appearance of motor dysfunction. Testosterone deficiency has been identified in some men with PD experiencing sexual dysfunction. Thermoregulatory dysfunction in PD has received even less attention than sexual dysfunction. Paroxysmal drenching sweats are reported by a number of people with PD. Sweating problems may be more likely to occur in PD patients experiencing motor fluctuations, but sweating episodes also can appear independent of motor status. This type of episodic hyperhidrosis can be tremendously embarrassing for individuals experiencing it and can significantly impact their quality of life. No effective pharmacologic treatment for the drenching sweats has been reported, but improvement after deep brain stimulation surgery has been described [28]. 5. Sleep disturbances Disturbed or impaired sleep is very common in the setting of PD and its prevalence may reach close to 90% [29]. The most common form of insomnia in PD is sleep fragmentation, with frequent nocturnal awakenings. The basis for sleep fragmentation in PD is multifactorial and may include impaired “turnability” due to nighttime rigidity and bradykinesia, nocturia, medication effects, periodic limb movements, and others. Effective treatment of sleep fragmentation is dependent upon identifying and then targeting the suspected source of the problem. REM sleep behavior disorder (RBD), characterized by continued ability to move during REM sleep, has gained considerable attention in recent years, both as a manifestation of PD and as a risk factor for the development of PD. The prevalence of RBD in PD isn't known with certainty, but may be in the range of 25e50%. RBD may be present years before the classic motor features of PD emerge. In fact, some studies suggest that individuals with RBD have an approximate 80e90% risk of eventually developing PD. It is important to identify PD patients with RBD because it is potentially dangerous, both to the patient and to the patient's bed partner, and effective treatment exists. 6. Fatigue The feeling of tiredness or exhaustion that characterizes fatigue has been increasingly recognized in the setting of PD. Fatigue often is identified by persons with PD as one of their most disabling symptoms with the greatest impact on their quality of life [30]. Little is known of the mechanism of fatigue in PD and effective treatment of fatigue in PD is lacking. 7. Summary NMS are now recognized as extremely frequent and important components of PD that can appear during all stages of the disorder, including the premotor stage. Beyond their importance in facilitating the diagnosis of PD, the fact that many NMS may respond to appropriate treatment makes it vital that neurologists are familiar
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with the NMS of PD and that they seek their presence by asking patients about them and, if present, that they then either initiate appropriate treatment or make appropriate referral for treatment of the NMS. The tendency to assume that someone else will manage these problems needs to be guarded against. Financial disclosures 2013e2015 Employment, Stock Ownership, Intellectual Property Rights Nothing to Disclose Royalties (for books edited) CRC Press (Taylor & Francis); Humana Press (Springer) Journal Editor Parkinsonism & Related Disorders Honoraria (for lectures) Teva, UCB, USWorldMeds Honoraria (for consulting) Pfizer, Chelsea, Acadia, Lundbeck, Clintara/Acorda Research Grants, Contracts None Legal Consulting Tucker Ellis & West; Thomas Thomas & Hafer References [1] H.-S. Kim, S.-M. Cheon, J.-W. Seo, H.-J. Ryu, K.-W. Park, J.W. Kim, Nonmotor symptoms more closely related to Parkinson's disease: comparison with normal elderly, J. Neurol. Sci. 324 (2013) 70e73. [2] S. Krishnan, G. Sarma, S. Sarma, A. Kishore, Do nonmotor symptoms in Parkinson's disease differ from normal aging? Mov. Disord. 26 (2011) 2110e2113. [3] T. Witjas, E. Kaphan, J.P. Azulay, O. Blin, M. Ceccaldi, J. Pouget, et al., Nonmotor fluctuations in Parkinson's disease: frequent and disabling, Neurology 59 (2002) 408e413. [4] T.K. Khoo, A.J. Yarnall, G.W. Duncan, S. Coleman, J.T. O'Brien, D.J. Brooks, et al., The spectrum of nonmotor symptoms in early Parkinson disease, Neurology 80 (2013) 276e281. [5] S.S. O'Sullivan, D.R. Williams, D.A. Gallagher, L.A. Massey, L. Silveira-Moriyama, A.J. Lees, Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study, Mov. Disord. 23 (2008) 101e106. [6] A. Storch, C.B. Schneider, M. Wolz, Y. Stürwald, A. Nebe, P. Odin, et al., Nonmotor fluctuations in Parkinson disease, Neurology 80 (2013) 800e809. [7] N.J. Weerkamp, G. Tissingh, P.J. Poels, S.U. Zuidema, M. Munneke, R.T. Koopmans, et al., Nonmotor symptoms in nursing home residents with Parkinson's disease: prevalence and effect on quality of life, J. Am. Geriatr. Soc. 61 (2013) 1714e1721. [8] F. Baig, M. Lawton, M. Rolinski, C. Ruffmann, K. Nithi, S.G. Evetts, et al., Delineating nonmotor symptoms in early Parkinson's disease and first-degree relatives, Mov. Disord. (2015) (epub ahead of print). [9] R.L. Doty, D.A. Deems, S. Stellar, Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease
duration, Neurology 38 (1988) 1237e1244. [10] S. Cavaco, A. Goncalves, A. Mendes, N. Vila-Ch~ a, I. Moreira, J. Fernandes, et al., Abnormal olfaction in Parkinson disease is related to faster disease progression, Behav. Neurol. 2015 (2015) 976589. [11] S. Casjens, A. Eckert, D. Woitalla, G. Ellrichmann, M. Turewicz, C. Stephan, et al., Diagnostic value of the impairment of olfaction in Parkinson's disease, PLoS One 8 (2013) e64735. [12] K. Knudsen, M. Flensborg Damholdt, K. Mouridsen, P. Borghammer, Olfactory function in Parkinson's disease e effects of training, Acta Neurol. Scand. (2015) (epub ahead of print). ski, K. Honczarenko, A. Potemkowski, K. Safranow, [13] B. Nowacka, W. Lubin Ophthalmological features of Parkinson disease, Med. Sci. Monit. 20 (2014) 2243e2249. [14] I. Bodis-Wollner, P.B. Kozlowski, S. Glazman, S. Miri, a-Synuclein in the inner retina in Parkinson disease, Ann. Neurol. 75 (2014) 964e966. [15] P. Valkovic, M. Minar, H. Singliarova, J. Harsany, M. Hanakova, J. Martinkova, et al., Pain in Parkinson's disease: a cross-sectional study of its prevalence, types, and relationship to depression and quality of life, PLoS One 10 (2015) e0136541. [16] J.S. Riejnders, U. Ehrt, W.E. Weber, D. Aarsland, A.F. Leentjens, A systematic review of prevalence studies of depression in Parkinson's disease, Mov. Disord. 23 (2008) 183e189. [17] Z. Qamhawi, D. Towey, B. Shah, G. Pagano, J. Seibyl, K. Marek, et al., Clinical correlates of raphe serotonergic dysfunction in early Parkinson's disease, Brain (2015) (epub ahead of print). [18] T. Simuni, H.H. Fernandez, Anxiety in Parkinson's disease, in: R.F. Pfeiffer, I. Bodis-Wollner (Eds.), Parkinson's Disease and Nonmotor Dysfunction, second ed., Humana Press, New York, 2013, pp. 17e29. [19] M.G. Den Brock, J.W. van Dalen, W.A. van Gool, E.P. Moll van Charante, R.M. de Bie, E. Richard, Apathy in Parkinson's disease: a systematic review and metaanalysis, Mov. Disord. 30 (2015) 759e769. [20] A. Meyer, R. Zimmermann, U. Gschwandtner, F. Hatz, H. Bousleiman, N. Schwarz, et al., Apathy in Parkinson's disease is related to executive function, gender and age but not to depression, Front. Aging Neurosci. 6 (2015) 350, http://dx.doi.org/10.3389/fnagi.2014.00350. [21] M.A. Hely, W.G. Reid, M.A. Adena, G.M. Halliday, J.G. Morris, The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years, Mov. Disord. 23 (2008) 837e844. [22] E. Stefanova, L. Ziropadja, T. Stojkovi c, I. Stankovi c, A. Tomi c, M. Je^ cmenicaLuki c, et al., Mild cognitive impairment in early Parkinson's disease using the movement disorder society task force criteria: cross-sectional study in Hoehn and Yahr stage 1, Dement. Geriatr. Cogn. Disord. 40 (2015) 199e209. [23] A.M. Hellman, S.P. Shah, S.M. Pawlowski, J.E. Duda, J.F. Morley, Continuous non-invasive monitoring to detect covert autonomic dysfunction in Parkinson's disease, Parkinsonism Relat. Disord. 21 (2015) 723e728. [24] A. Fasano, N.P. Visanji, L.W. Liu, A.E. Lang, R.F. Pfeiffer, Gastrointestinal dysfunction in Parkinson's disease, Lancet Neurol. 14 (2015) 625e639. [25] K. Winge, Lower urinary tract dysfunction in patients with parkinsonism and other neurodegenerative disorders, Handb. Clin. Neurol. 130 (2015) 335e356. [26] R. Sakakibara, J. Panicker, E. Finazzi-Agro, V. Iacovelli, H. Bruschini, The Parkinson’s Disease Subcommittee, The Neurourology Promotion Committee in the International Continence Society, A guideline for the management of bladder dysfunction in Parkinson's disease and other gait disorders, Neurourol. Urodyn. (2015) (epub ahead of print). [27] G. Bronner, O.S. Cohen, G. Yahalom, E. Kozlova, Y. Orlev, N. Molshatzki, et al., Correlates of quality of sexual life in male and female patients with Parkinson disease and their partners, Parkinsonism Relat. Disord. 20 (2014) 1085e1088. [28] E. Trachani, C. Constantoyannis, V. Sirrou, Z. Kefalopoulou, E. Markaki, E. Chroni, Effects of subthalamic nucleus deep brain stimulation on sweating function in Parkinson's disease, Clin. Neurol. Neurosurg. 112 (2010) 213e217. [29] M.M. Kurtis, C. Rodriguez-Blazquez, P. Martinez-Martin, ELEP Group. Relationship between sleep disorders and other non-motor symptoms in Parkinson's disease, Parkinsonism Relat. Disord. 19 (2013) 1152e1155. [30] V.B. Dogan, A. Koksal, A. Dirican, S. Baybas, A. Dirican, G.B. Dogan, Independent effect of fatigue on health-related quality of life in patients with idiopathic Parkinson's disease, Neurol. Sci. (2015) (epub ahead of print).
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