- Email: [email protected]
Non-motor symptoms: Identification and management
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 13 (2007) S450–S456 www.elsevier.com/locate/parkreldis
Non-motor symptoms: Identification and management Sharon Muzerengia,b , Donatella Contrafattoc , K. Ray Chaudhuria,b,d, * a University
Hospital Lewisham, London, UK Disorders Unit, King’s College Hospital, Denmark Hill, London, UK c Department of Neurosciences, University of Catania, Italy d National Parkinson Foundation Centre of Excellence, King’s College, London, UK b Movement
Abstract Non-motor symptoms are an important part of Parkinson’s disease (PD) symptoms complex. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Treatment of non-motor symptoms can be challenging as these symptoms are often unresponsive to conventional dopaminergic therapy. However, awareness that these symptoms are related to PD is vital as research into treatment and causation will be the cornerstone for delivering a comprehensive modern treatment for PD. © 2007 Elsevier B.V. All rights reserved. Keywords: Parkinson’s Disease; Non-motor symptoms; Treatment
1. Introduction
2. Neuropsychiatric symptoms
The non-motor symptom (NMS) complex is a key part of Parkinson’s disease (PD), and several studies have shown that these symptoms are highly prevalent in PD. In a recent study to validate the non-motor symptoms questionnaire (NMSQuest), NMS symptoms such as sleep dysfunction, depression, anxiety and fatigue were more common in PD patients compared to age-matched controls [1].NMS are present across all disease stages but the frequency increases with disease progression. Several studies have shown that NMS have a major impact on the quality of life ahead of motor symptoms of PD [2]. Awareness and recognition of non-motor symptoms has improved in recent years with studies focussing on development and validation of NMS assessment tools such as the non-motor symptoms questionnaire (NMS Quest) and non-motor symptoms scale (NMSS) [2,3]. Table 1 presents an overview of the NMS complex, and Table 2 summarises the different assessment tools for various non-motor symptoms. Some NMS do not respond to the conventional dopaminergic treatment suggesting involvement of other neurotransmitters other than the dopaminergic pathway. Although limited, evidence is now available from controlled studies for treatment of some NMS. In this paper we discuss various treatment strategies for NMS of PD.
Neuropsychiatric symptoms are very common in patients with PD, and their impact on the quality of life of patients and caregivers and on the rate of institutionalization and health economics is very high. They range from anxiety, depression, and apathy to psychosis and frank dementia, and may result in significant disability.
* Corresponding author. Movement Disorders Unit, 9th Floor Ruskin Wing, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: +44 0207 346 8336; fax : +44 0208 333 3093. E-mail address: [email protected] (K.R. Chaudhuri). 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
2.1. Depression Depression in PD has a high prevalence, affecting up to 45% of patients [5]. It may precede the onset of the cardinal motor symptoms of PD by years. Despite this, the disorder is very often under-recognized by physicians even in a specialist setting, since many symptoms, such as anhedonia, lack of motivation, flat mood, overlap with core features of PD, besides the frequently contemporary occurrence of dementia, may interfere with the rating of depression. However, the identification of mood disturbances is crucial, since it is well known that depression is the most significant predictor of quality of life in PD patients [2,6]. Hence, it is very important to identify scales for the identification and the rating of depression that are suitable for PD patients and easy to use. Recently, the Movement Disorder Society commissioned a task force to assess the validity of the existing scales for depression and make clinical recommendations regarding their use in PD patients [7]. For measurement of severity of depressive symptoms, the Hamilton Depression Scale (HAM-D), the ˚ Montgomery–Asberg Depression Rating Scale (MADRS),
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
S451
Table 1 NMS complex a Neuropsychiatric symptoms
Depression, apathy, anxiety Anhedonia Attention deficit Hallucinations, Illusion, Delusions Dementia Obsessional behaviour (usually drug induced), repetitive behaviour Confusion Delirium (could be drug induced) Panic attacks
Sleep Disorders
Restless legs and Periodic limb movements REM behaviour disorder and REM loss of atonia Non REM sleep related movement disorders Excessive daytime somnolence Vivid dreaming Insomnia Sleep Disordered breathing
Autonomic symptoms
Bladder disturbances Urgency Nocturia Frequency Sweating Orthostatic hypotension (OH) Falls related to (OH) Coat Hanger pain Sexual dysfunction Hypersexuality (likely to be drug induced) Erectile impotence Dry eyes (xerostomia)
Gastrointestinal symptoms (also overlaps with autonomic)
Dribbling of saliva Ageusia Dysphagia/Choking Reflux, Vomiting Nausea Constipation Unsatisfactory voiding of bowel Faecal incontinence
Sensory symptoms
Pain Paraesthesia Olfactory disturbance
Other symptoms
Fatigue Diplopia Blurred vision Seborrhoea Weight loss Weight gain (possibly drug induced)
a
Taken from ref. [4].
the Beck Depression Inventory (BDI), and the Zung SelfRating Depression Scale (SDS) scales are recommended. For screening purposes, HAM-D, BDI, MADRS, Hospital Anxiety and Depression Scale (HADS), and Geriatric Depression Scale (GDS) are valid. Observer-rated scales (e.g., HAM-D and MADRS) are preferred if the study or clinical situation permits. Several studies seem to suggest that the pathophysiology underlying mood disorders in PD may be different from the mechanisms that account for the behavioral symptoms observed in the general population. PD depression may be
related to the pathology of PD itself, and it could be the result of damage to serotoninergic neurotransmission and to limbic noradrenergic and dopaminergic mechanisms that occur in the course of disease [8]. This suggests that specific trials with antidepressant drugs are required in PD. There is some evidence supporting the use of tricyclic agents, in particular amitriptyline, for the treatment of depression in PD [9]. Nevertheless, the anti-cholinergic side effects, especially the orthostatic hypotension and the possible worsening of cognitive function, represent an important limit to their use. Even if clear evidence to
S452
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456 Table 2 Assessment tools for various NMS NMS
Assessment tools
All NMS
NMSQuest, NMSS
Sleep
Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS), SCOPA sleep, Pittsburgh Sleep Quality Index (PSQI)
Depression
Hamilton Depression Scale (HAM-D), ˚ Montgomery–Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Zung Self-Rating Depression Scale (SDS), Hospital Anxiety and Depression Scale (HADS), Geriatric Depression Scale (GDS)
Fatigue
Parkinson’s Disease Fatigue Scale (PFS16), Fatigue Severity Scale (FSS)
Apathy
Lille Apathy Rating Scale (LARS), Marin Apathy Evaluation Scale
Cognitive impairment
Cambridge Cognitive Examination (CAMCog), Mini-Mental State Examination (MMSE)
Psychosis and visual hallucinations
DSM-IV (not validated in PD), Parkinson Psychosis Rating Scale (PPRS), Scales for Outcomes in Parkinson’s disease – Psychiatric Complications (SCOPA-PC)
support or refute the use of other antidepressant treatments in PD patients is not available, it should be considered that drugs such as selective serotonine reuptake inhibitors (SSRI) and new antidepressants (reboxetine, venlafaxine) are less likely to cause severe side effects; however, the risk of potentially fatal serotonin syndrome with the concomitant use of SSRIs and monoamine oxidase inhibitors, such as selegiline, must be remembered. The anti-depressant effect of dopaminergic drugs has often been reported. One trial comparing the efficacy of pramipexole versus pergolide in the treatment of depression in PD showed an improvement in the depression scores in both groups, but patients treated with pramipexole had improved significantly more than patients treated with pergolide [10]. A small recent study, conducted on 15 patients to examine the feasibility of treating depressed PD patients with a modified individual cognitive-behavioral treatment, shows significant reduction in depressive symptoms and negative cognitions [11]. 2.2. Anxiety and apathy Anxiety disorders, such as panic attack, social phobia and generalized anxiety disorder, are often reported in early PD, and represent a possible preclinical sign of the disease. Apathy, which can be described as reduced emotion, diminished motivation and lack of initiative, is a common finding in patients with PD; its prevalence varies from 16.5% to 42%, depending on the assessment tools and the population characteristics [12]. A dysfunction of the
frontal–subcortical circuits, which are involved in motivation and reward, appears to play an important role in the pathogenesis of apathy [13]. Nevertheless, the clear association between apathy and cognitive impairment, as well as recent evidence indicating the beneficial effects of cholinesterase inhibitors not only on cognitive dysfunction but also on apathy, seems to suggest the involvement of nondopaminergic circuits in general and of cholinergic system in particular in the genesis of apathetic behavior [12]. Many scales used for depression lack apathy-related items, so the use of specific scales for the detection and differentiation between several dimensions of apathy is recommended, such as the Lille Apathy Rating Scale (LARS) and the Marin Apathy Evaluation Scale. 2.3. Cognitive impairment Dementia affects about 40% or more of patients with PD; the incidence of dementia in these patients is up to six times that in healthy people [14]. Its presence is an important predictor of nursing home placement and is associated with a shorter survival. Several features have been consistently reported as risk factors for dementia: age at onset, duration of the disease, akinetic–rigid syndrome, severity of motor impairment, depression, and atypical neurological features (such as early occurrence of autonomic failure, symmetrical disease presentation, moderate response to dopaminergic treatment and early occurrence of psychosis) [14]. Typically dementia in PD has the profile of a dysexecutive syndrome, with impairment of attention and ability to
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
plan, problem-solve and regulate goal-directed behavior; the language deficits described in PD, such as impaired verbal fluency and naming difficulty, may be due to the above-mentioned executive dysfunction. However, some PD patients may develop another type of dementia, with a limbic or hippocampal type amnesia; these individuals may be patients in whom AD and PD coexist [14]. The diagnosis of dementia in PD patients may be difficult, since it is required to differentiate if the impairment in cognitive domains and in daily-living activities is primary due to the cognitive dysfunction or to the motor status and the possible concomitant depression and psychosis. The Cambridge Cognitive Examination (CAMCog) and the Mini-Mental State Examination (MMSE) have been demonstrated to be useful and quick screening tools for the detection of DSM-defined dementia, with high sensitivities (95% and 98% respectively) and specificities (94% and 77 %) [9]. Levodopa has a limited effect on cognitive impairment in PD, and can cause confusion and psychosis in demented patients. Some antiparkinsonian drugs, such as anticholinergics and amantadine, can interfere with cognitive function and worsen the underlying dementia, therefore their discontinuation should be considered [15]. There is some evidence that cholinesterase inhibitors might be beneficial in the treatment of dementia in PD. Rivastigmine (up to 12 mg/day) is probably effective in improving cognitive function and behavioral symptoms in patients with PD and dementia or with Lewy Body Disease, but the magnitude of the benefit is modest and tremor may be exacerbated although UPDRS scores did not change. For patients with PD-dementia, donepezil is probably effective in improving cognitive function, but the cognitive benefit is small. There is insufficient evidence to support or refute the benefit of piracetam on PD-dementia [9,15]. To date there is no evidence of efficacy of the glutamate receptor modulator memantine. 2.4. Psychosis and visual hallucinations Visual hallucinations are the most common psychotic symptoms in PD, usually well formed, consisting of people or animals, and less commonly inanimate objects; usually they are not disruptive and can occur many times a day in advanced stages of disease. Auditory (such as indistinct whispers or music, threatening voices), tactile, olfactory and gustatory hallucinations are relatively uncommon and generally co-occur with visual hallucinations. More sinister symptoms, such as delusions, paranoid ideation and delirium, are rare but become more frequent as the disease progresses, and their development is supposed to be a consequence of antiparkinson medications (drug-induced psychosis). The prevalence of psychosis varies widely in different studies, but in clinic-based samples of patients on dopaminergic therapy, several studies suggest it ranges from 25% to 30%.
S453
There is no gold standard for the diagnosis of psychosis in PD; evidence is limited to one study in which a Parkinson Psychosis Rating Scale (PPRS) was administered to 29 patients with PD and psychosis; there were positive results for several clinimetric measures of the PPRS, but, since patients without psychosis were not included, the specificity of this screening tool in PD cannot be determined [16]. DSM-IV criteria for psychosis have not been validated in PD. Recently, provisional criteria for the diagnosis of psychosis in PD were proposed, whose key points are: characteristic symptoms, chronology of onset and duration of symptoms, exclusionary diagnoses, associated features such as dementia [17]. Because of the possible role of antiparkinson treatment in inducing psychosis, interventions are primarily based on reduction or withdrawal of the offending drugs. Reduction/stop of antidepressants and anxiolytics is recommended as first line of action; eventually reduction of antiparkinsonian drugs with withdrawal of anticholinergics, amantadine, and finally dopamine agonists, MAO-B and COMT inhibitors should be considered, although it can cause the worsening of the motor status. However, infection and metabolic disorders can trigger psychosis and, in such cases, the underlying disorder should be treated. Complementary treatment with atypical antipsychotics is sometimes necessary. Clozapine, whose efficacy is well documented, is recommended, but it requires monitoring since its use can be associated with severe adverse events: agranulocytosis is rare but potentially fatal, and the absolute neutrophil count must be monitored. Quetiapine may be considered since it is supposed to be safe and does not require monitoring, even if the data on its efficacy are still insufficient. Olanzapine and risperidone are not recommended, since they worsen the motor status of PD patients. The cholinesterase inhibitors rivastigmine and donepezil have been reported to improve psychosis in PD patients; motor worsening was reported in few cases, and the most frequent adverse events were increased tremor, nausea or vomiting [9,15].
3. Gastro-intestinal symptoms Constipation, often associated with a sensation of incomplete evacuation, is one of the most frequent non-motor symptoms, and can precede the onset of the disease by many years. The mechanism underlying it is multifactorial, involving both colon motility and ano-rectal dysfunction. Constipation does not respond well to dopaminergic treatment, suggesting that non-dopaminergic mechanisms could be implicated. Prolonged treatment with classic laxatives is not recommended in clinical practice as these substances may lead to electrolyte imbalance (hypokalemia) and atonic colon. Recently some studies suggested the use of macrogol, which
S454
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
osmotically increases water retention and softens stool in the colon, for the treatment of constipation in PD. A recent small double-blind, placebo-controlled study showed the efficacy of this isosmotic solution, which appeared to be well-tolerated and did not lead to changes in the course of PD [18]. Some gastrointestinal symptoms, such as nausea, anorexia, dysphagia and reduced gastric motility, are very common, and sometimes they occur as side effect of dopaminergic treatment. The use of domperidone, a peripheral dopaminergic blocker, is recommended. Metoclopramide is another drug that blocks peripheral dopamine receptors, but it crosses the blood–brain barrier, blocking also central dopaminergic receptors; it can increase Parkinsonism so its use should be avoided in PD patients [15]. Dribbling of saliva is very common in PD and neurodegenerative disorders, often underestimated by physicians even if it represent one of the most disabling symptoms, a source of social embarrassment. Injections of botulinum toxin type A into the parotid gland constitute an effective treatment [19].
4. Sensory symptoms Hyposmia affects 90% of PD patients, and seems to be unrelated to the stage of disease or the actual treatment. It was hypothesized that the detection of hyposmia could be a useful tool to identify the population at risk or to distinguish PD from other parkinsonian syndromes. The University of Pennsylvania smell identification test (UPSIT), a selfadministered test, is very often used in trials to demonstrate reduction of olfaction in PD and non-PD subjects, but some of the smells are not familiar for non-North-American subjects; Sniffin Sticks is used in European countries and is an easy and cheap test. Pain is very common in PD; it can have secondary causes, such as radicular problems, stiffness of shoulders and neck, dystonia or muscle cramps. However, painful sensations non-related to any apparent disorders, usually localized in the most affected side, have also been reported. A positron emission tomography (PET) study in which pain threshold before and after administration of levodopa was compared in PD patients and in controls found that the nociceptive threshold was lower in PD patients and returned to normal ranges after levodopa administration. It was hypothesized that the basal ganglia and the dopaminergic system participate in processing nociceptive information [20]. However, in clinical experiences central pain seems to be poorly responsive to dopaminergic treatments, and it often requires specific treatments.
5. Sleep disorders Sleep disorders are a common presentation in Parkinson’s disease (PD), affecting up to 90% of patients [21]. They
cause disability, reduced daytime functioning and poor quality of life ahead of motor symptoms. Identification and treatment of sleep problems is essential as these disorders when untreated have a negative impact on the quality of life. The aetiology of sleep disorders in Parkinson’s disease is multifactorial, including the neurochemical and neurodegenerative changes of the disease, dopaminergic therapy, and symptoms such as nocturnal akinesia, nocturia, and depression. Sleep disorders can be easily identified by clinical interview and by using validated bedside assessment tools such as Non-motor symptoms scale (NMSS), Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS) and Scales for Outcomes in Parkinson’s disease – sleep (SCOPA sleep), Pittsburgh Sleep Quality Index (PSQI). Use of diagnostic tests such as polysomnography or multiple sleep latency tests is also essential for making a definitive diagnosis. Robust evidence is available for treatment of nocturnal NMS such as restless legs syndrome (RLS) and REM sleep behaviour disorder (RBD). Several controlled studies have shown that dopamine agonists are effective in treating RLS, however there are no specific trials for RLS in Parkinson’s disease. Clonazepam is highly effective for treatment of RBD and is now used as the first-line therapy. Evidence comes from an open label study of 93 cases with RBD where 87% of the patients reported partial or complete resolution of symptoms after treatment with clonazepam [21]. Another study reported an improvement in RBD symptoms in eight patients treated with melatonin and continued benefit over 12 months; indications for use of melatonin included lack of response or intolerance to clonazepam and cognitive impairment [22]. In a recent case series of 10 patients with RBD, pramipexole reduced or resolved RBD symptoms in 89% of the patients and had maintained efficacy for up to 25 months; the rationale for using pramipexole was the hypothesis of dopaminergic dysfunction in the aetiology of RBD [23]. Further studies involving larger numbers of patients are required. Modafinil has become the mainstay of treatment for excessive daytime sleepiness in PD. In two double-blind randomised controlled trials to assess efficacy of modafinil in treating excessive daytime sleepiness, modafinil was reported to be more effective compared to placebo [24,25]. However another study involving 40 patients with excessive daytime sleepiness failed to show a significant benefit with modafinil [26]. Deep brain stimulation was reported to improve RLS symptoms in 6 patients [27]. However, in a previous retrospective study re-emergence of RLS symptoms was reported in 11 patients who had undergone STN-DBS due to reduction in dopaminergic medication [28]. Chronic STN-DBS also improves nocturnal motor disturbances such as akinesia and early morning dystonia, resulting in increased total sleep time [29].
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
S455
6. Autonomic dysfunction
7. Fatigue
Autonomic dysfunction is another common non-motor complication in Parkinsonian syndromes. The spectrum of dysautonomia includes orthostatic hypotension, bladder dysfunction, hyperhydrosis, erectile dysfunction and gastrointestinal problems. Such symptoms were reported to have a high prevalence in PD patients compared to controls in a study by Magerkurth et al. [30]. Orthostatic hypotension can occur as a complication of antiparkinsonian therapy.
Fatigue is a common NMS associated with depressive symptoms and sleep dysfunction, however it is now recognised as an independent symptom in PD. Involvement of other pathways other than the dopaminergic system is thought to contribute to the development of fatigue in Parkinson’s disease as it responds poorly to dopaminergic medication. Antifatigue effects of modafinil in neurological disorders have been reported, and methylphenidate has been shown to improve fatigue scores significantly [36].
6.1. Orthostatic hypotension The initial step in treatment of postural hypotension may include nonpharmacological interventions such as increasing salt intake intake, wearing elastic stockings and avoiding aggravating factors. Large meals have been reported to induce postprandial hypotension, and warning patients about this is therefore essential. Other precipitating factors include hot weather and antihypertensive agents [15]. Pharmacological treatment includes use of fludrocortisone, which facilitates renal sodium reabsoption and potassium excretion, thus increasing blood volume. Fludrocortisone has been shown to be effective for treatment of postural hypotension in various studies [15]. Alpha-adrenergic agonists such as midodrine cause a significant increase in blood pressure as shown in two studies [31,32]. Although there is insufficient evidence for treatment of hypotension in PD, indomethacin and dihydroergotamine, etilefrine hydrochloride and erythropoietin may be useful [15].
8. Conclusion NMS are often under-recognised by physicians. Identifying these symptoms is essential and some of them are treatable. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Evaluation of the NMS complex should be done routinely in clinical practice as they have been shown to have a negative impact on quality of life ahead of motor symptoms. We therefore recommend the use of assessment tools such as the NMS Questionnaire and Non-motor Scale.
Acknowledgement Funding: Parkinson’s Disease Nonmotor Group.
6.2. Bladder dysfunction Nocturia, incontinence, frequency and urgency are common complaints in PD patients. The pathophysiology in PD is unclear although functional imaging studies suggests that dopaminergic mechanisms may be involved [33]. General measures such as avoiding fluid intake before bedtime may be useful for nocturia, urgency and incontinence. Anticholinergic drugs such as oxybutinin, alpha-1 agonists (e.g. prazosin) and antispasmodics (tolterodine) are effective for treating urinary incontinence, however there are no specific trials in PD [15]. In a small study involving eight patients, intranasal desmopressin significantly reduced the frequency of nocturnal voiding [34]. Further clinical trials with large groups of patients are required to evaluate the effectiveness of these drugs in Parkinson’s disease. 6.3. Erectile dysfunction Erectile dysfunction and reduced sex drive have been described as part of dysautonomia in Parkinson’s disease. Sildenafil, a phosphodiesterase inhibitor was proven in treating erectile dysfunction in clinical trials [35]. Other studies have shown that dopamine agonists such as apormorphine given before sexual activity and pergolide may improve erectile function in patients with Parkinson’s disease [15].
Conflict of Interest statement None declared.
References [1] Chaudhuri KR, Martinez-Martin P, Schapira A, Stocchi F, Sethi K, Odin P, et al. An international multicentre pilot study of the first comprehensive non-motor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Mov Disord 2006;21(7):916−23. [2] Global Parkinson’s disease Survey Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord 2002;17(1):60−7. [3] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov Disord 2007;22(13):1901−11. [4] Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson’s Disease: diagnosis and management. Lancet Neurol 2006; 5(3):235−45. [5] Burn DJ. Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord 2002;17:445−54. [6] Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000;69:308−12).
S456
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
[7] Schrag A, Barone P, Brown RG, Leentjens AFG, McDonald WM, Starkstein S, et al. Depression Rating Scales in Parkinson’s Disease: Critique and Recommendations. Mov Disord 2007;22(8):1077−92. [8] Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervations in the limbic system. Brain 2005;128:1314−22. [9] Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, et al. Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66(7):996–1002. [10] Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova Z, et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 2003;10:399–406. [11] Dobkin R, Allen LA, Menza M. Cognitive-behavioral therapy for depression in Parkinson’s disease: a pilot study. Mov Disord 2007; 22(7):946−52. [12] Dujardin K, Sockeel P, Devos D, Delliaux M, Krystkowiak P, Dest´ee A, et al. Characteristics of apathy in Parkinson’s disease. Mov Disord 2007;22(6):778−84. [13] Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873−80. [14] Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol 2003;2:229−37. [15] Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late complicated) Parkinson’s disease. Eur J Neurol 2006;13:1186– 202. [16] Friedberg G, Zoldan J, Weizman A, Melamed E. Practice parameter. Parkinson Psychosis Rating Scale: a practical instrument for grading psychosis in Parkinson’s disease. Clin Neuropharmacol1998;21:280−4. [17] Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, et al. Diagnostic criteria for psychosis in Parkinson’s disease: Report of an NINDS, NIMH Work Group B. Mov Disord 2007;22(8):1061−8. [18] Zangaglia R, Martignoni E, Glorioso M, Ossola M, Riboldazzi G, Calandrella D, et al. Macrogol for the treatment of constipation in Parkinson’s disease. A randomized placebo-controlled study. Mov. Disord 2007;22(9):1239−44. [19] Lagalla G, Millevolte M, Capecci M, Provinciali L, Ceravolo MG. Botulinum Toxin Type A for drooling in Parkinson’s Disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2006;21(5):704−7. [20] Brefel-Courbon C, Payoux P, Thalamas C, Ory F, Quelven I, Chollet F, et al. Effect of levodopa on pain threshold in Parkinson’s disease: a clinical and positron emission tomography study. Mov Disord 2005; 20(12):1557−63.
[21] Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123:331−9. [22] Boeve BF.Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003;4(4):281−4. [23] Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behaviour disorder: results from a case series. Sleep Med 2006; 7(5):418−23. [24] Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomised trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003;18(3):287−93. [25] Hogl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Ulmer H, et al. Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25(8):905−9. [26] Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76(12):1636−9. [27] Driver-Dunckley E, Evidente VG, Adler CH et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord. 2006;21(8):1287−9. [28] Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology 2004;63(12):2410−2. [29] Lyons KE, Pahwa R. Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness and early morning dystonia in patients with Parkinson’s disease. J Neurosurg 2006;104(4):502−5. [30] Magerkurth C, Schnitzer R, Braune S. Symptoms of autonomic failure in Parkinson’s disease: prevalence and impact on daily life. Clin Auton Res 2005;15:76−82. [31] Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, et al. Neurogenic orthostatic hypotension: a doubleblind placebo-controlled study with midodrine. Am J Med 1993;95:38−48. [32] Low PA, Gilden FL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized double blind multicenter study. Midodrine study group. J Am Med Assoc 1997;277:1046−51. [33] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. Mov Disord 2006;21(6):737−45. [34] Suchowersky I, Furtado S, Rohs G. Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 1995;10:337−40. [35] Raffaele R, Vecchio I, Giammusso B, Morgia G, Brunettoa MB, Rampelloa L, et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson’s disease. Eur Urol 2002;41:382−6. [36] Mendon¸ca DA, Menezes K, Jog MS. Methylphenidate improves fatigue scores in Parkinson’s disease: A randomised controlled trial. Mov Disord 2007;22(14):2070−6.
Non-motor symptoms: Identification and management Sharon Muzerengia,b , Donatella Contrafattoc , K. Ray Chaudhuria,b,d, * a University
Hospital Lewisham, London, UK Disorders Unit, King’s College Hospital, Denmark Hill, London, UK c Department of Neurosciences, University of Catania, Italy d National Parkinson Foundation Centre of Excellence, King’s College, London, UK b Movement
Abstract Non-motor symptoms are an important part of Parkinson’s disease (PD) symptoms complex. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Treatment of non-motor symptoms can be challenging as these symptoms are often unresponsive to conventional dopaminergic therapy. However, awareness that these symptoms are related to PD is vital as research into treatment and causation will be the cornerstone for delivering a comprehensive modern treatment for PD. © 2007 Elsevier B.V. All rights reserved. Keywords: Parkinson’s Disease; Non-motor symptoms; Treatment
1. Introduction
2. Neuropsychiatric symptoms
The non-motor symptom (NMS) complex is a key part of Parkinson’s disease (PD), and several studies have shown that these symptoms are highly prevalent in PD. In a recent study to validate the non-motor symptoms questionnaire (NMSQuest), NMS symptoms such as sleep dysfunction, depression, anxiety and fatigue were more common in PD patients compared to age-matched controls [1].NMS are present across all disease stages but the frequency increases with disease progression. Several studies have shown that NMS have a major impact on the quality of life ahead of motor symptoms of PD [2]. Awareness and recognition of non-motor symptoms has improved in recent years with studies focussing on development and validation of NMS assessment tools such as the non-motor symptoms questionnaire (NMS Quest) and non-motor symptoms scale (NMSS) [2,3]. Table 1 presents an overview of the NMS complex, and Table 2 summarises the different assessment tools for various non-motor symptoms. Some NMS do not respond to the conventional dopaminergic treatment suggesting involvement of other neurotransmitters other than the dopaminergic pathway. Although limited, evidence is now available from controlled studies for treatment of some NMS. In this paper we discuss various treatment strategies for NMS of PD.
Neuropsychiatric symptoms are very common in patients with PD, and their impact on the quality of life of patients and caregivers and on the rate of institutionalization and health economics is very high. They range from anxiety, depression, and apathy to psychosis and frank dementia, and may result in significant disability.
* Corresponding author. Movement Disorders Unit, 9th Floor Ruskin Wing, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: +44 0207 346 8336; fax : +44 0208 333 3093. E-mail address: [email protected] (K.R. Chaudhuri). 1590-8658/ $ – see front matter © 2007 Elsevier B.V. All rights reserved.
2.1. Depression Depression in PD has a high prevalence, affecting up to 45% of patients [5]. It may precede the onset of the cardinal motor symptoms of PD by years. Despite this, the disorder is very often under-recognized by physicians even in a specialist setting, since many symptoms, such as anhedonia, lack of motivation, flat mood, overlap with core features of PD, besides the frequently contemporary occurrence of dementia, may interfere with the rating of depression. However, the identification of mood disturbances is crucial, since it is well known that depression is the most significant predictor of quality of life in PD patients [2,6]. Hence, it is very important to identify scales for the identification and the rating of depression that are suitable for PD patients and easy to use. Recently, the Movement Disorder Society commissioned a task force to assess the validity of the existing scales for depression and make clinical recommendations regarding their use in PD patients [7]. For measurement of severity of depressive symptoms, the Hamilton Depression Scale (HAM-D), the ˚ Montgomery–Asberg Depression Rating Scale (MADRS),
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
S451
Table 1 NMS complex a Neuropsychiatric symptoms
Depression, apathy, anxiety Anhedonia Attention deficit Hallucinations, Illusion, Delusions Dementia Obsessional behaviour (usually drug induced), repetitive behaviour Confusion Delirium (could be drug induced) Panic attacks
Sleep Disorders
Restless legs and Periodic limb movements REM behaviour disorder and REM loss of atonia Non REM sleep related movement disorders Excessive daytime somnolence Vivid dreaming Insomnia Sleep Disordered breathing
Autonomic symptoms
Bladder disturbances Urgency Nocturia Frequency Sweating Orthostatic hypotension (OH) Falls related to (OH) Coat Hanger pain Sexual dysfunction Hypersexuality (likely to be drug induced) Erectile impotence Dry eyes (xerostomia)
Gastrointestinal symptoms (also overlaps with autonomic)
Dribbling of saliva Ageusia Dysphagia/Choking Reflux, Vomiting Nausea Constipation Unsatisfactory voiding of bowel Faecal incontinence
Sensory symptoms
Pain Paraesthesia Olfactory disturbance
Other symptoms
Fatigue Diplopia Blurred vision Seborrhoea Weight loss Weight gain (possibly drug induced)
a
Taken from ref. [4].
the Beck Depression Inventory (BDI), and the Zung SelfRating Depression Scale (SDS) scales are recommended. For screening purposes, HAM-D, BDI, MADRS, Hospital Anxiety and Depression Scale (HADS), and Geriatric Depression Scale (GDS) are valid. Observer-rated scales (e.g., HAM-D and MADRS) are preferred if the study or clinical situation permits. Several studies seem to suggest that the pathophysiology underlying mood disorders in PD may be different from the mechanisms that account for the behavioral symptoms observed in the general population. PD depression may be
related to the pathology of PD itself, and it could be the result of damage to serotoninergic neurotransmission and to limbic noradrenergic and dopaminergic mechanisms that occur in the course of disease [8]. This suggests that specific trials with antidepressant drugs are required in PD. There is some evidence supporting the use of tricyclic agents, in particular amitriptyline, for the treatment of depression in PD [9]. Nevertheless, the anti-cholinergic side effects, especially the orthostatic hypotension and the possible worsening of cognitive function, represent an important limit to their use. Even if clear evidence to
S452
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456 Table 2 Assessment tools for various NMS NMS
Assessment tools
All NMS
NMSQuest, NMSS
Sleep
Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS), SCOPA sleep, Pittsburgh Sleep Quality Index (PSQI)
Depression
Hamilton Depression Scale (HAM-D), ˚ Montgomery–Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Zung Self-Rating Depression Scale (SDS), Hospital Anxiety and Depression Scale (HADS), Geriatric Depression Scale (GDS)
Fatigue
Parkinson’s Disease Fatigue Scale (PFS16), Fatigue Severity Scale (FSS)
Apathy
Lille Apathy Rating Scale (LARS), Marin Apathy Evaluation Scale
Cognitive impairment
Cambridge Cognitive Examination (CAMCog), Mini-Mental State Examination (MMSE)
Psychosis and visual hallucinations
DSM-IV (not validated in PD), Parkinson Psychosis Rating Scale (PPRS), Scales for Outcomes in Parkinson’s disease – Psychiatric Complications (SCOPA-PC)
support or refute the use of other antidepressant treatments in PD patients is not available, it should be considered that drugs such as selective serotonine reuptake inhibitors (SSRI) and new antidepressants (reboxetine, venlafaxine) are less likely to cause severe side effects; however, the risk of potentially fatal serotonin syndrome with the concomitant use of SSRIs and monoamine oxidase inhibitors, such as selegiline, must be remembered. The anti-depressant effect of dopaminergic drugs has often been reported. One trial comparing the efficacy of pramipexole versus pergolide in the treatment of depression in PD showed an improvement in the depression scores in both groups, but patients treated with pramipexole had improved significantly more than patients treated with pergolide [10]. A small recent study, conducted on 15 patients to examine the feasibility of treating depressed PD patients with a modified individual cognitive-behavioral treatment, shows significant reduction in depressive symptoms and negative cognitions [11]. 2.2. Anxiety and apathy Anxiety disorders, such as panic attack, social phobia and generalized anxiety disorder, are often reported in early PD, and represent a possible preclinical sign of the disease. Apathy, which can be described as reduced emotion, diminished motivation and lack of initiative, is a common finding in patients with PD; its prevalence varies from 16.5% to 42%, depending on the assessment tools and the population characteristics [12]. A dysfunction of the
frontal–subcortical circuits, which are involved in motivation and reward, appears to play an important role in the pathogenesis of apathy [13]. Nevertheless, the clear association between apathy and cognitive impairment, as well as recent evidence indicating the beneficial effects of cholinesterase inhibitors not only on cognitive dysfunction but also on apathy, seems to suggest the involvement of nondopaminergic circuits in general and of cholinergic system in particular in the genesis of apathetic behavior [12]. Many scales used for depression lack apathy-related items, so the use of specific scales for the detection and differentiation between several dimensions of apathy is recommended, such as the Lille Apathy Rating Scale (LARS) and the Marin Apathy Evaluation Scale. 2.3. Cognitive impairment Dementia affects about 40% or more of patients with PD; the incidence of dementia in these patients is up to six times that in healthy people [14]. Its presence is an important predictor of nursing home placement and is associated with a shorter survival. Several features have been consistently reported as risk factors for dementia: age at onset, duration of the disease, akinetic–rigid syndrome, severity of motor impairment, depression, and atypical neurological features (such as early occurrence of autonomic failure, symmetrical disease presentation, moderate response to dopaminergic treatment and early occurrence of psychosis) [14]. Typically dementia in PD has the profile of a dysexecutive syndrome, with impairment of attention and ability to
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
plan, problem-solve and regulate goal-directed behavior; the language deficits described in PD, such as impaired verbal fluency and naming difficulty, may be due to the above-mentioned executive dysfunction. However, some PD patients may develop another type of dementia, with a limbic or hippocampal type amnesia; these individuals may be patients in whom AD and PD coexist [14]. The diagnosis of dementia in PD patients may be difficult, since it is required to differentiate if the impairment in cognitive domains and in daily-living activities is primary due to the cognitive dysfunction or to the motor status and the possible concomitant depression and psychosis. The Cambridge Cognitive Examination (CAMCog) and the Mini-Mental State Examination (MMSE) have been demonstrated to be useful and quick screening tools for the detection of DSM-defined dementia, with high sensitivities (95% and 98% respectively) and specificities (94% and 77 %) [9]. Levodopa has a limited effect on cognitive impairment in PD, and can cause confusion and psychosis in demented patients. Some antiparkinsonian drugs, such as anticholinergics and amantadine, can interfere with cognitive function and worsen the underlying dementia, therefore their discontinuation should be considered [15]. There is some evidence that cholinesterase inhibitors might be beneficial in the treatment of dementia in PD. Rivastigmine (up to 12 mg/day) is probably effective in improving cognitive function and behavioral symptoms in patients with PD and dementia or with Lewy Body Disease, but the magnitude of the benefit is modest and tremor may be exacerbated although UPDRS scores did not change. For patients with PD-dementia, donepezil is probably effective in improving cognitive function, but the cognitive benefit is small. There is insufficient evidence to support or refute the benefit of piracetam on PD-dementia [9,15]. To date there is no evidence of efficacy of the glutamate receptor modulator memantine. 2.4. Psychosis and visual hallucinations Visual hallucinations are the most common psychotic symptoms in PD, usually well formed, consisting of people or animals, and less commonly inanimate objects; usually they are not disruptive and can occur many times a day in advanced stages of disease. Auditory (such as indistinct whispers or music, threatening voices), tactile, olfactory and gustatory hallucinations are relatively uncommon and generally co-occur with visual hallucinations. More sinister symptoms, such as delusions, paranoid ideation and delirium, are rare but become more frequent as the disease progresses, and their development is supposed to be a consequence of antiparkinson medications (drug-induced psychosis). The prevalence of psychosis varies widely in different studies, but in clinic-based samples of patients on dopaminergic therapy, several studies suggest it ranges from 25% to 30%.
S453
There is no gold standard for the diagnosis of psychosis in PD; evidence is limited to one study in which a Parkinson Psychosis Rating Scale (PPRS) was administered to 29 patients with PD and psychosis; there were positive results for several clinimetric measures of the PPRS, but, since patients without psychosis were not included, the specificity of this screening tool in PD cannot be determined [16]. DSM-IV criteria for psychosis have not been validated in PD. Recently, provisional criteria for the diagnosis of psychosis in PD were proposed, whose key points are: characteristic symptoms, chronology of onset and duration of symptoms, exclusionary diagnoses, associated features such as dementia [17]. Because of the possible role of antiparkinson treatment in inducing psychosis, interventions are primarily based on reduction or withdrawal of the offending drugs. Reduction/stop of antidepressants and anxiolytics is recommended as first line of action; eventually reduction of antiparkinsonian drugs with withdrawal of anticholinergics, amantadine, and finally dopamine agonists, MAO-B and COMT inhibitors should be considered, although it can cause the worsening of the motor status. However, infection and metabolic disorders can trigger psychosis and, in such cases, the underlying disorder should be treated. Complementary treatment with atypical antipsychotics is sometimes necessary. Clozapine, whose efficacy is well documented, is recommended, but it requires monitoring since its use can be associated with severe adverse events: agranulocytosis is rare but potentially fatal, and the absolute neutrophil count must be monitored. Quetiapine may be considered since it is supposed to be safe and does not require monitoring, even if the data on its efficacy are still insufficient. Olanzapine and risperidone are not recommended, since they worsen the motor status of PD patients. The cholinesterase inhibitors rivastigmine and donepezil have been reported to improve psychosis in PD patients; motor worsening was reported in few cases, and the most frequent adverse events were increased tremor, nausea or vomiting [9,15].
3. Gastro-intestinal symptoms Constipation, often associated with a sensation of incomplete evacuation, is one of the most frequent non-motor symptoms, and can precede the onset of the disease by many years. The mechanism underlying it is multifactorial, involving both colon motility and ano-rectal dysfunction. Constipation does not respond well to dopaminergic treatment, suggesting that non-dopaminergic mechanisms could be implicated. Prolonged treatment with classic laxatives is not recommended in clinical practice as these substances may lead to electrolyte imbalance (hypokalemia) and atonic colon. Recently some studies suggested the use of macrogol, which
S454
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
osmotically increases water retention and softens stool in the colon, for the treatment of constipation in PD. A recent small double-blind, placebo-controlled study showed the efficacy of this isosmotic solution, which appeared to be well-tolerated and did not lead to changes in the course of PD [18]. Some gastrointestinal symptoms, such as nausea, anorexia, dysphagia and reduced gastric motility, are very common, and sometimes they occur as side effect of dopaminergic treatment. The use of domperidone, a peripheral dopaminergic blocker, is recommended. Metoclopramide is another drug that blocks peripheral dopamine receptors, but it crosses the blood–brain barrier, blocking also central dopaminergic receptors; it can increase Parkinsonism so its use should be avoided in PD patients [15]. Dribbling of saliva is very common in PD and neurodegenerative disorders, often underestimated by physicians even if it represent one of the most disabling symptoms, a source of social embarrassment. Injections of botulinum toxin type A into the parotid gland constitute an effective treatment [19].
4. Sensory symptoms Hyposmia affects 90% of PD patients, and seems to be unrelated to the stage of disease or the actual treatment. It was hypothesized that the detection of hyposmia could be a useful tool to identify the population at risk or to distinguish PD from other parkinsonian syndromes. The University of Pennsylvania smell identification test (UPSIT), a selfadministered test, is very often used in trials to demonstrate reduction of olfaction in PD and non-PD subjects, but some of the smells are not familiar for non-North-American subjects; Sniffin Sticks is used in European countries and is an easy and cheap test. Pain is very common in PD; it can have secondary causes, such as radicular problems, stiffness of shoulders and neck, dystonia or muscle cramps. However, painful sensations non-related to any apparent disorders, usually localized in the most affected side, have also been reported. A positron emission tomography (PET) study in which pain threshold before and after administration of levodopa was compared in PD patients and in controls found that the nociceptive threshold was lower in PD patients and returned to normal ranges after levodopa administration. It was hypothesized that the basal ganglia and the dopaminergic system participate in processing nociceptive information [20]. However, in clinical experiences central pain seems to be poorly responsive to dopaminergic treatments, and it often requires specific treatments.
5. Sleep disorders Sleep disorders are a common presentation in Parkinson’s disease (PD), affecting up to 90% of patients [21]. They
cause disability, reduced daytime functioning and poor quality of life ahead of motor symptoms. Identification and treatment of sleep problems is essential as these disorders when untreated have a negative impact on the quality of life. The aetiology of sleep disorders in Parkinson’s disease is multifactorial, including the neurochemical and neurodegenerative changes of the disease, dopaminergic therapy, and symptoms such as nocturnal akinesia, nocturia, and depression. Sleep disorders can be easily identified by clinical interview and by using validated bedside assessment tools such as Non-motor symptoms scale (NMSS), Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS) and Scales for Outcomes in Parkinson’s disease – sleep (SCOPA sleep), Pittsburgh Sleep Quality Index (PSQI). Use of diagnostic tests such as polysomnography or multiple sleep latency tests is also essential for making a definitive diagnosis. Robust evidence is available for treatment of nocturnal NMS such as restless legs syndrome (RLS) and REM sleep behaviour disorder (RBD). Several controlled studies have shown that dopamine agonists are effective in treating RLS, however there are no specific trials for RLS in Parkinson’s disease. Clonazepam is highly effective for treatment of RBD and is now used as the first-line therapy. Evidence comes from an open label study of 93 cases with RBD where 87% of the patients reported partial or complete resolution of symptoms after treatment with clonazepam [21]. Another study reported an improvement in RBD symptoms in eight patients treated with melatonin and continued benefit over 12 months; indications for use of melatonin included lack of response or intolerance to clonazepam and cognitive impairment [22]. In a recent case series of 10 patients with RBD, pramipexole reduced or resolved RBD symptoms in 89% of the patients and had maintained efficacy for up to 25 months; the rationale for using pramipexole was the hypothesis of dopaminergic dysfunction in the aetiology of RBD [23]. Further studies involving larger numbers of patients are required. Modafinil has become the mainstay of treatment for excessive daytime sleepiness in PD. In two double-blind randomised controlled trials to assess efficacy of modafinil in treating excessive daytime sleepiness, modafinil was reported to be more effective compared to placebo [24,25]. However another study involving 40 patients with excessive daytime sleepiness failed to show a significant benefit with modafinil [26]. Deep brain stimulation was reported to improve RLS symptoms in 6 patients [27]. However, in a previous retrospective study re-emergence of RLS symptoms was reported in 11 patients who had undergone STN-DBS due to reduction in dopaminergic medication [28]. Chronic STN-DBS also improves nocturnal motor disturbances such as akinesia and early morning dystonia, resulting in increased total sleep time [29].
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
S455
6. Autonomic dysfunction
7. Fatigue
Autonomic dysfunction is another common non-motor complication in Parkinsonian syndromes. The spectrum of dysautonomia includes orthostatic hypotension, bladder dysfunction, hyperhydrosis, erectile dysfunction and gastrointestinal problems. Such symptoms were reported to have a high prevalence in PD patients compared to controls in a study by Magerkurth et al. [30]. Orthostatic hypotension can occur as a complication of antiparkinsonian therapy.
Fatigue is a common NMS associated with depressive symptoms and sleep dysfunction, however it is now recognised as an independent symptom in PD. Involvement of other pathways other than the dopaminergic system is thought to contribute to the development of fatigue in Parkinson’s disease as it responds poorly to dopaminergic medication. Antifatigue effects of modafinil in neurological disorders have been reported, and methylphenidate has been shown to improve fatigue scores significantly [36].
6.1. Orthostatic hypotension The initial step in treatment of postural hypotension may include nonpharmacological interventions such as increasing salt intake intake, wearing elastic stockings and avoiding aggravating factors. Large meals have been reported to induce postprandial hypotension, and warning patients about this is therefore essential. Other precipitating factors include hot weather and antihypertensive agents [15]. Pharmacological treatment includes use of fludrocortisone, which facilitates renal sodium reabsoption and potassium excretion, thus increasing blood volume. Fludrocortisone has been shown to be effective for treatment of postural hypotension in various studies [15]. Alpha-adrenergic agonists such as midodrine cause a significant increase in blood pressure as shown in two studies [31,32]. Although there is insufficient evidence for treatment of hypotension in PD, indomethacin and dihydroergotamine, etilefrine hydrochloride and erythropoietin may be useful [15].
8. Conclusion NMS are often under-recognised by physicians. Identifying these symptoms is essential and some of them are treatable. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Evaluation of the NMS complex should be done routinely in clinical practice as they have been shown to have a negative impact on quality of life ahead of motor symptoms. We therefore recommend the use of assessment tools such as the NMS Questionnaire and Non-motor Scale.
Acknowledgement Funding: Parkinson’s Disease Nonmotor Group.
6.2. Bladder dysfunction Nocturia, incontinence, frequency and urgency are common complaints in PD patients. The pathophysiology in PD is unclear although functional imaging studies suggests that dopaminergic mechanisms may be involved [33]. General measures such as avoiding fluid intake before bedtime may be useful for nocturia, urgency and incontinence. Anticholinergic drugs such as oxybutinin, alpha-1 agonists (e.g. prazosin) and antispasmodics (tolterodine) are effective for treating urinary incontinence, however there are no specific trials in PD [15]. In a small study involving eight patients, intranasal desmopressin significantly reduced the frequency of nocturnal voiding [34]. Further clinical trials with large groups of patients are required to evaluate the effectiveness of these drugs in Parkinson’s disease. 6.3. Erectile dysfunction Erectile dysfunction and reduced sex drive have been described as part of dysautonomia in Parkinson’s disease. Sildenafil, a phosphodiesterase inhibitor was proven in treating erectile dysfunction in clinical trials [35]. Other studies have shown that dopamine agonists such as apormorphine given before sexual activity and pergolide may improve erectile function in patients with Parkinson’s disease [15].
Conflict of Interest statement None declared.
References [1] Chaudhuri KR, Martinez-Martin P, Schapira A, Stocchi F, Sethi K, Odin P, et al. An international multicentre pilot study of the first comprehensive non-motor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Mov Disord 2006;21(7):916−23. [2] Global Parkinson’s disease Survey Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord 2002;17(1):60−7. [3] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov Disord 2007;22(13):1901−11. [4] Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson’s Disease: diagnosis and management. Lancet Neurol 2006; 5(3):235−45. [5] Burn DJ. Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson’s disease. Mov Disord 2002;17:445−54. [6] Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000;69:308−12).
S456
S. Muzerengi et al. / Parkinsonism and Related Disorders 13 (2007) S450–S456
[7] Schrag A, Barone P, Brown RG, Leentjens AFG, McDonald WM, Starkstein S, et al. Depression Rating Scales in Parkinson’s Disease: Critique and Recommendations. Mov Disord 2007;22(8):1077−92. [8] Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervations in the limbic system. Brain 2005;128:1314−22. [9] Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, et al. Practice Parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66(7):996–1002. [10] Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova Z, et al. Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 2003;10:399–406. [11] Dobkin R, Allen LA, Menza M. Cognitive-behavioral therapy for depression in Parkinson’s disease: a pilot study. Mov Disord 2007; 22(7):946−52. [12] Dujardin K, Sockeel P, Devos D, Delliaux M, Krystkowiak P, Dest´ee A, et al. Characteristics of apathy in Parkinson’s disease. Mov Disord 2007;22(6):778−84. [13] Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873−80. [14] Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol 2003;2:229−37. [15] Horstink M, Tolosa E, Bonuccelli U, Deuschl G, Friedman A, Kanovsky P, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late complicated) Parkinson’s disease. Eur J Neurol 2006;13:1186– 202. [16] Friedberg G, Zoldan J, Weizman A, Melamed E. Practice parameter. Parkinson Psychosis Rating Scale: a practical instrument for grading psychosis in Parkinson’s disease. Clin Neuropharmacol1998;21:280−4. [17] Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D, et al. Diagnostic criteria for psychosis in Parkinson’s disease: Report of an NINDS, NIMH Work Group B. Mov Disord 2007;22(8):1061−8. [18] Zangaglia R, Martignoni E, Glorioso M, Ossola M, Riboldazzi G, Calandrella D, et al. Macrogol for the treatment of constipation in Parkinson’s disease. A randomized placebo-controlled study. Mov. Disord 2007;22(9):1239−44. [19] Lagalla G, Millevolte M, Capecci M, Provinciali L, Ceravolo MG. Botulinum Toxin Type A for drooling in Parkinson’s Disease: a double-blind, randomized, placebo-controlled study. Mov Disord 2006;21(5):704−7. [20] Brefel-Courbon C, Payoux P, Thalamas C, Ory F, Quelven I, Chollet F, et al. Effect of levodopa on pain threshold in Parkinson’s disease: a clinical and positron emission tomography study. Mov Disord 2005; 20(12):1557−63.
[21] Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123:331−9. [22] Boeve BF.Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003;4(4):281−4. [23] Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behaviour disorder: results from a case series. Sleep Med 2006; 7(5):418−23. [24] Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomised trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003;18(3):287−93. [25] Hogl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Ulmer H, et al. Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25(8):905−9. [26] Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson’s disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76(12):1636−9. [27] Driver-Dunckley E, Evidente VG, Adler CH et al. Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation. Mov Disord. 2006;21(8):1287−9. [28] Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease. Neurology 2004;63(12):2410−2. [29] Lyons KE, Pahwa R. Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness and early morning dystonia in patients with Parkinson’s disease. J Neurosurg 2006;104(4):502−5. [30] Magerkurth C, Schnitzer R, Braune S. Symptoms of autonomic failure in Parkinson’s disease: prevalence and impact on daily life. Clin Auton Res 2005;15:76−82. [31] Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, et al. Neurogenic orthostatic hypotension: a doubleblind placebo-controlled study with midodrine. Am J Med 1993;95:38−48. [32] Low PA, Gilden FL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized double blind multicenter study. Midodrine study group. J Am Med Assoc 1997;277:1046−51. [33] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. Mov Disord 2006;21(6):737−45. [34] Suchowersky I, Furtado S, Rohs G. Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson’s disease. Mov Disord 1995;10:337−40. [35] Raffaele R, Vecchio I, Giammusso B, Morgia G, Brunettoa MB, Rampelloa L, et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson’s disease. Eur Urol 2002;41:382−6. [36] Mendon¸ca DA, Menezes K, Jog MS. Methylphenidate improves fatigue scores in Parkinson’s disease: A randomised controlled trial. Mov Disord 2007;22(14):2070−6.