Non-motor symptoms in parkinson’s disease

European Journal of Neurology 2008, 15 (Suppl. 1): 14–20 Non-motor symptoms in ParkinsonÕs disease W. PoeweDepartment of Neurology, Medical University of Innsbruck, Innsbruck, Austria Although still considered a paradigmatic movement disorder, ParkinsonÕs disease (PD) is associated with a broad spectrum of non-motor symptoms. These include disorders of mood and affect with apathy, anhedonia and depression, cognitive dys- function and hallucinosis, as well as complex behavioural disorders. Sensory dys- function with hyposmia or pain is almost universal, as are disturbances of sleep–wakecycle regulation. Autonomic dysfunction including orthostatic hypotension, urogeni- tal dysfunction and constipation is also present to some degree in a majority of patients. Whilst overall non-motor symptoms become increasingly prevalent withadvancing disease, many of them can also antedate the first occurrence of motor signs– most notably depression, hyposmia or rapid eye movement sleep behaviour disorder(RBD). Although exact clinicopathological correlations for most of these non-motorfeatures are still poorly understood, the occurrence of constipation, RBD or hyposmiaprior to the onset of clinically overt motor dysfunction would appear consistent withthe ascending hypothesis of PD pathology proposed by Braak and colleagues.
Screening these early non-motor features might, therefore, be one approach towardsearly ÔpreclinicalÕ diagnosis of PD. This review article provides an overview of theclinical spectrum of non-motor symptoms in PD together with a brief review oftreatment options.
side effects such as orthostatic hypotension, hallucina- tions, somnolence, insomnia or leg oedema, adding to Idiopathic ParkinsonÕs disease (PD) is generally con- the overall burden of the non-motor spectrum of par- sidered a paradigmatic movement disorder, as most kinsonian morbidity. Recently, it has also become patients present with one or more of the cardinal motor clearer that in PD, non-motor dysfunction may actually features. Current treatment strategies focus on dopa- antedate overt signs and symptoms of motor distur- mine replacement to correct at least partially the dis- bance [5]. A recent hypothesis about neuropathological turbances of movement caused by striatal dopamine stages of PD suggests that Lewy body pathology in the deficiency. However, it has long been recognized that nigrostiatal system only develops after lower brainstem the neuropathology underlying PD involves many brain areas and the olfactory system have become affected [1].
areas beyond the dopaminergic nigrostriatal system, This has led to clinical studies assessing olfactory dys- including areas that are not directly involved in motor function or rapid eye movement (REM) sleep beha- control such as the locus coeruleus, the dorsal vagal viour disorder (RBD) as potential risk factors for later nucleus, the raphe nuclei of the brainstem, the hypo- development of PD in otherwise asymptomatic indi- thalamus, the olfactory tubercle and large parts of the viduals [6,7]. Independent of their role as early or limbic cortex and the neocortex [1, 2]. Pathology also ÔpreclinicalÕ markers, the non-motor symptoms of PD extends into the peripheral autonomic nervous system become increasingly prevalent and obvious over the involving sympathetic ganglia, cardiac sympathetic course of the illness and are a major determinant of efferents and the myenteric plexus of the gut [2]. It is, quality of life, progression of overall disability and therefore, not surprising that the majority of patients with PD, if not all of them, reveal a variety of non-motor symptoms, either as spontaneous complaint or upon specific questioning [3,4]. In addition, drugs usedto treat motor symptoms frequently induce non-motor Non-motor symptoms in PD involve a multitude offunctions including sleep–wake cycle regulation, cog-nitive function, regulation of mood and hedonistic tone, Correspondence: Prof. W. Poewe, Department of Neurology, Medical autonomic nervous system function as well as sensory University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria function and pain perception (see Table 1). In their (tel.: +43 512 504 23850; fax: +43 512 504 23852; e-mail: werner.
[email protected]).
various combinations, they may eventually become the Ó 2008 The AuthorJournal compilation Ó 2008 EFNS Non-motor symptoms in ParkinsonÕs disease Table 1 Non-motor features of ParkinsonÕs disease Table 2 Non-motor symptoms during wearing-off in patients withfluctuating ParkinsonÕs disease (from Witjas et al. [12]) Frontal executive dysfunctionDementia and psychosis Orthostatic hypotensionUrogenital dysfunctionConstipation specific to PD, but has also been reported in multiple system atrophy (MSA) patients, although it appears to differentiate between vascular parkinsonism and PD and has also been absent in parkin disease [16,17].
RBD, rapid eye movement sleep behaviour disorder; PLMS, periodic Hyposmia does not appear to progress over the course limb movements in sleep; RLS, restless legs syndrome.
of PD, but is present from the start of the illness.
Recent data suggest that idiopathic hyposmia inasymptomatic first-degree relatives of PD patients is associated with an increased risk to develop overt PD and may thus be an early preclinical sign or even a riskmarker for the general population [6].
Painful sensations not explained by osteoarthritic con-ditions, neuropathy or other causes of pain commonly Autonomic dysfunction is an almost universal feature observed in elderly populations have been reported in of PD and includes orthostatic hypotension, urinary 40–50% of patients with PD in different series [9–12].
and sexual dysfunction as well as constipation [3].
PD-related pain may be a presenting symptom whenpatients complain of aching shoulder pain on the side initially affected by rigidity and loss of dexterity, notuncommonly leading to orthopaedic referrals and Retrospective chart reviews in a large series of 135 cases occasionally even shoulder surgery for suspected of pathologically proven PD found evidence for impingement or lesions to the rotator cuff. Sensory symptomatic orthostatic hypotension in life in 30% of symptoms and pain are also prominent in fluctuating cases, bladder dysfunction in 32% and constipation in PD, where tingling or burning sensations, neuralgic 36% [4]. Senard et al. [18], when studying 91 patients pain or diffuse pain have been described as common with idiopathic PD in a cardiovascular laboratory with ÔoffÕ-period phenomena in one study [12] (see Table 2).
tilt table examinations, found systolic blood pressure The pathophysiology underlying painful sensations in drops of >20 mmHg in 58% of their patients. In 20% PD are poorly understood, but may include alterations of cases, orthostatic hypotension was symptomatic, and in central pain-processing pathways, as suggested by symptomatic orthostatic hypotension correlated with one recent study describing decreased heat pain dopaminergic medication dose on the one hand and thresholds in PD patients [13], which were more marked duration and severity of PD on the other hand [18].
on the side initially and more severely affected by the Compared with MSA, symptomatic orthostatic hypo- tension is a late feature in PD. Wenning et al. [19], in a Defective odour detection and discrimination is a small series of postmortem-confirmed cases of PD and sensory abnormality which appears to affect some 90% MSA, found mean latencies to symptomatic orthostatic of patients with PD [14] and has been related to neu- hypotension of 24 months in 15 patients with MSA, ropathology affecting the olfactory bulbs [15]. Hypos- compared with 166 months in 11 patients with PD.
mia is generally marked when formally tested, although Mechanisms of orthostatic hypotension may differ many patients do not spontaneously complain of it.
between MSA and PD: whilst the central autonomic Within the spectrum of parkinsonism, hyposmia is not nervous system bears the brunt of pathology related to Ó 2008 The AuthorJournal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20 autonomic failure in MSA, peripheral sympathetic Management of autonomic failure in PD is largely cardiovascular denervation is prominent in PD, as based on pragmatic recommendations without firm shown in multiple studies of cardiac MIBG (metaiod- evidence for efficacy from controlled clinical trials. The obenzylguanidine) scintigraphy in both disorders [20].
measures most commonly used are summarized in Autonomic failure is also prominent in patients with pathologically proven dementia with Lewy bodies(DLB). Dysautonomia was found in 28 of 29 patients with pathologically proven DLB [21]. A recent studyhas provided evidence that orthostatic hypotension is Contrary to James ParkinsonÕs original descriptions more pronounced in PD patients with dementia than in about Ôthe senses and intellect being uninjuredÕ, PD is PD patients without dementia. In a small cardiovas- clearly associated with a variety of alterations in mood, cular function study, Peralta et al. [22] found systolic initiative, hedonistic tone and cognitive functioning (see blood pressure drops upon head-up tilt in 50% of patients with PD and dementia as compared with only7% of patients without clinically defined dementia.
These observations in PD dementia and DLB suggest apotential link with the spread of Lewy body pathology Loss of initiative and assertiveness as well as anhedonia to neocortical and limbic structures and parts of the and anxiety are common complaints and findings in peripheral autonomic nervous system.
patients with PD. The reported prevalence of majordepression in PD ranges from a low of 4% to a high of70% with a mean of about 40% [29,30]. This figure has been confirmed by more recent studies showing the Lewy body pathology in the peripheral autonomic presence of depressive symptoms in 36–50% of patients nervous system in PD also includes the myenteric with PD [31]. It has been suggested that the majority of plexus with subsequent colonic sympathetic denerva- depressed PD patients meet criteria for major depres- tion [23]. Clinically, this is associated with a high sion according to DSM-IV [32], whilst more recent prevalence of prolonged intestinal transit time and series suggest that this percentage may actually be much constipation in PD. Several case–control studies havereported increased prevalence of constipation in PD ofbetween 28% and 61% as compared with controls Table 3 Practical management of autonomic dysfunction in (6–33%) [24–26] and one series even found either con- stipation or prolonged intestinal transit time in 80% ofpatients with PD [27]. Importantly, constipation has been reported as a prominent complaint before onset of overt motor symptoms in about half of the patients in one series [25]. In line with such observations, a large prospective follow-up study in 6790 male participants in the Honolulu Heart Programme found evidence for a 2.7–4.5 fold increase in relative risk for PD in males with <1 bowel movement per day as compared with subjects with one, two or more movements per day [28].
Similar to hyposmia, constipation may, therefore, turn out to be one of the earliest symptoms of Lewy body Urogenital dysfunction in PD includes erectile and 50 mg sildenafil (caveat: orthostatic hypotension)10 mg vardenafil ejaculatory failure, urinary frequency and urgency, incomplete bladder emptying, double micturition and urge incontinence. Similar to orthostatic hypotension, urogenital failure is a late feature of PD, with mean latencies of 144 vs. 12 months in MSA in one post- Ensure adequate fluidAdd laxatives (macrogol) Journal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20 Non-motor symptoms in ParkinsonÕs disease Table 4 Neuropsychiatric features of ParkinsonÕs disease The development of dementia has a significant impact on the natural history of PD and has been shown to be associated with more rapid progression of disability, increased risk for nursing home place- ment and increased mortality [37–39]. The underlying pathology may include Alzheimer-type changes, cor- tical Lewy body degeneration and vascular lesions, but Lewy body degeneration has been suggested to be the major driving factor for the development of dementia in PD [36]. The clinical profile of PD DA dysregulation syndrome (hedonistic homeostatic dementia includes aspects of psychomotor slowing, retrieval, impaired set-shifting, problem-solving, poorvisuospatial function, fluctuations in attention andcognition, as well as prominent mood and personality lower, with the majority of patients presenting with disorders, hallucinosis and psychosis, whilst language symptoms of Ôminor depressionÕ or Ôdysthymic disorderÕ and praxis remain largely intact [40]. Recently, one [33]. Patients with PD and depressive symptoms gen- large and several small-scale randomized, placebo- erally show less self-blame, guilt and sense of failure controlled trials have suggested efficacy of cholines- and fewer self-destructive thoughts than patients with terase inhibition in improving cognitive function, as primary major depression, and they rarely commit well as erratic and psychotic behaviour in patients suicide [30]. On the other hand, features of anxiety and with PD dementia [41,42]. Whether or not DLB is a panic attacks are frequently encountered, as is loss of distinct clinical entity from PD dementia is currently interest and initiative, fatigue, indecisiveness and anhedonia. Depressive episodes or panic attacks havebeen found to precede the onset of motor symptoms in Whilst some of the depressive symptoms in PD may Hallucinosis and psychotic episodes are amongst the actually occur as a reaction at the time of first diag- most challenging of the parkinsonian non-motor nosis, there is general consensus that PD-specific symptoms. Although there are few systematic and pathology with multiple transmitter deficiencies in prospective studies of incidence and risk factors for mesocortical monoaminergic systems play a major role, psychosis in PD, recent drug trials in early PD have including the mesocorticolimbic dopamine projection found incidences of hallucinosis and psychosis in up as well as the mesocortical noradrenergic and seroto- to 17% of patients [43], and cross-sectional surveys in outpatient clinic populations have reported a 40%prevalence of hallucinations in PD [44]. Psychosis hasbeen identified as a major risk factor for nursing home placement in PD [38], and early psychotic Subtle cognitive deficits are almost universally identified reactions to dopaminergic replacement in PD have even in early PD upon detailed neuropsychological been correlated with subsequent development of testing [34]. They relate to frontal executive dysfunction cognitive decline and dementia [45]. Drug-induced with impaired problem-solving and defective planning psychosis in PD is more common in elderly patients and organization of goal-directed behaviour, as well as than those with cognitive impairment. Hallucinosis difficulties with set shifting, visuospatial deficits and and psychosis can be triggered by all major classes of some impairment of learning and memory [35]. Com- antiparkinsonian agents including dopamine agonists, munity-based studies have suggested that some 30–40% levodopa, monoamine oxidase B inhibitors, amanta- of patients with PD will develop clinically defined dine and anticholinergics. Several randomized con- dementia. A recent meta-analysis of prevalence studies trolled studies suggest that dopamine agonists are on dementia in PD has estimated that 31% of PD more probably to induce hallucinosis than levodopa patients fulfil the diagnostic criteria for dementia and [43,46]. The clinical spectrum of psychosis in PD that PD dementia accounts for around 4% of degen- includes visual illusions, visual hallucinations with erative dementias and may have a population-based retained insight, as well as florid paranoid hallucina- prevalence of between 0.2% and 0.5% in people tory psychosis and delusions. Visual phenomena are the predominant type of hallucinations in PD and Ó 2008 The AuthorJournal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20 they are usually well formed, colourful and rich in Management of sleep disorders in PD is complex and detail. Acoustic and tactile hallucinations are less have to target underlying mechanisms. Dopamine common and, if present, usually occur in association agonists may be helpful in sleep fragmentation because with visual hallucinations [47]. Currently, clozapine remains the only drug with proven antipsychotic effi- Clonazepam may be considered in RBD, and continu- cacy without motor worsening, as shown by placebo- ous positive airway pressure in some patients. Atypical controlled, randomized trials in PD. Quetiapine may neuroleptics or cholinesterase inhibitors may improve be a safer option, but its efficacy has not been sleep in patients with nocturnal episodes of confusion established in placebo-controlled studies. Olanzapine or hallucinosis. Modafinil has some success in patients has been shown to induce marked motor worsening with EDS. Usually, mechanisms are multiple and without evidence of efficacy in several randomized treatment multimodal. Overall, sleep problems in PD controlled studies. Cholinesterase inhibitors may be an remain a major therapeutic challenge.
important management alternative in PD dementia.
Non-motor symptoms are universal features of idio- Sleep disorders are amongst the most frequent non- pathic PD and involve dysfunction in the neuropsy- motor problems of PD [48]. They include difficulties chiatric, sensory and autonomic domains. In sum, falling asleep, frequent awakenings, nocturnal cramp- they add significantly to the overall disability caused ing, painful dystonia, or nocturnal motor symptoms by PD and are critical determinants of health-related with difficulties turning in bed, motor restlessness or quality of life. In the era of effective symptomatic clear-cut restless legs syndrome (RLS), night-time therapies for the motor symptoms of PD, non-motor incontinence, nocturnal confusion, hallucinosis and dysfunction has developed into a major prognostic daytime sleepiness. The awareness of the clinical factor for overall disease burden and everyday func- implications of these disturbances has only increased in tion in PD. In addition, there is increasing evidence recent years, prompting new research.
that non-motor dysfunction antedates clinical mani- Multiple contributing factors and clinical manifesta- festations of the motor symptoms of PD by years or tions are involved. The motor abnormalities of par- even decades and may thus turn out to be a critical kinsonism, e.g. nocturnal tremor, nocturnal akinesia, target for early diagnosis paradigms and identification ÔoffÕ-period dystonia, and RLS or periodic limb move- of at-risk populations. Besides defining predictive ments in sleep (PLMS) are possible causes. PD-related values of certain types of non-motor dysfunction neurodegeneration impacts the sleep structure. This including hyposmia, RBD or autonomic dysfunction, induces sleep fragmentation, reduced sleep efficiency, future research must focus on the development of reduced slow-wave sleep, reduced REM sleep and effective symptomatic therapies for PD non-motor RBD. Respiratory disturbances and autonomic distur- bances are other possible mechanisms.
An RBD is a pathological sleep structure character- ized by loss of REM sleep muscle atonia with phasic ortonic activity in the chin and extremity electromyogra- WP declares no conflicts of interest.
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