Non-motor symptom complex and comorbidities

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Non-motor symptom complex and comorbidities

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Non-motor symptom complex and comorbidities
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Non-motor symptom complex of Parkinson’s disease
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Nearly all patients with Parkinson’s disease (PD) experience non-motor symptoms at some stage of the disease.[Goldman & Holden, 2014] Psychiatric symptoms are the most frequent non-motor symptoms, reported by approximately two-thirds of patients with PD.[Goldman & Holden, 2014] These symptoms may include dementia, psychosis, depression, anxiety, apathy, impulse control disorders, and fatigue.[Goldman & Holden, 2014] 

Psychosis and dementia are often found together in PD, and both contribute to reduced quality of life, increase the risk of morbidity and mortality, and reduce the ability of patients to perform everyday tasks and live independently.[Goldman & Holden, 2014] 
PD is associated with numerous non-motor symptoms caused by damage to the autonomic nervous system, leading to impaired control of internal organs, such as the bladder, gastrointestinal tract, and the blood.[Pfeiffer, 2016] 

It can be difficult to know whether or not non-motor symptoms are directly attributable to PD-related neurodegeneration, since many of the symptoms are found in people of a similar age without the disease.[Pfeiffer, 2016] Some authors, therefore, refer to non-motor symptoms as PD-associated ‘comorbidities’ – i.e., health problems that occur at the same time as PD – rather than ‘symptoms’.[Litvan et al., 2012] 

Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol 2014; 16 (3): 281.

Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society task force guidelines. Mov Disord 2012; 27 (3): 349–356.

Pfeiffer RF. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2016; (Suppl 1): S119–S122.

Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009; 24 (11): 1641–1649.

Lim SY, Lang AE. The nonmotor symptoms of Parkinson’s disease – an overview. Mov Disord 2010; 25 (Suppl 1): S123–130. 

Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Mov Disord 2011; 26 (3): 399–406.

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Commonly experienced non-motor symptoms of Parkinson’s disease
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The non-motor symptoms of PD can be grouped into four domains: autonomic (including gastrointestinal, genitourinary, and cardiovascular symptoms), sleep disorders; neuropsychiatric disorders; and sensory and other symptoms (including pain and fatigue).[Erro et al., 2015; Schapira et al., 2017] Many of these symptoms are treatable, mostly with drug therapy, but sometimes with non-pharmacological approaches.[Erro et al., 2015; Schapira et al., 2017]

Patients with PD often under-report their non-motor symptoms, even though they can have a markedly negative effect on quality of life.[Erro et al., 2015] This may be because patients are embarrassed to raise these issues, or they may be unaware that their non-motor symptoms are related to PD.[Erro et al., 2015] Routine screening of patients with validated questionnaires may help to identify and treat symptoms effectively, as they arise.[Chaudhuri et al., 2015; Parkinson’s UK, 2017]

Chaudhuri KR, Sauerbier A, Rojo JM, et al. The burden of non-motor symptoms in Parkinson’s disease using a self-completed non-motor questionnaire: a simple grading system. Parkinsonism Relat Disord 2015; 21 (3): 287–291. 

Erro R, Santangelo G, Barone P, Vitale C. Nonmotor symptoms of Parkinson’s disease: classification and management. J Parkinson Restless Leg Synd 2015; 5: 1–10.

Parkinson’s UK website. Non-motor symptoms questionnaire (‘NMSQuest’). https://www.parkinsons.org.uk/sites/default/files/publications/download/.... Accessed February 2017.

Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci 2017; 18 (7): 435–450.

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The impact of non-motor symptoms on quality of life
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One of the main principles of caring for patients with PD is to preserve quality of life as much as possible, particularly during the later stages of the disease.[Prakash et al., 2016] Historically, the focus of clinical care has been on control of motor symptoms but, more recently, there has been greater recognition that non-motor symptoms also need to be identified and treated.[Prakash et al., 2016] 
Not all non-motor symptoms have an equal impact of quality of life, however.[Prakash et al., 2016] Studies suggest that sleep disorders – and the fatigue they can lead to – are common and have a significant negative impact on quality of life.[Prakash et al., 2016] Mood disorders and cognitive decline are also particularly important determinants of quality of life in people living with PD, both patients and caregivers.[Connolly & Fox, 2014; Jones et al., 2017; Prakash et al., 2016; Lim et al., 2017]

Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease. Neurotherapeutics 2014; 11 (1): 78–91.

Jones AJ, Kuijer RG, Livingston L, et al. Caregiver burden is increased in Parkinson’s disease with mild cognitive impairment (PD-MCI). Transl Neurodegener 2017; 6: 17.

Lim SY, Tan AH, Fox SH, et al. Integrating patient concerns into Parkinson’s disease management. Curr Neurol Neurosci Rep 2017; 17 (1): 3.

Prakash KM, Nadkarni NV, Lye WK, et al. The impact of non-motor symptoms on the quality of life of Parkinson’s disease patients: a longitudinal study. Eur J Neurol 2016; 23 (5): 854–860.

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

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Cognitive symptoms of Parkinson’s disease
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Cognition and cognitive impairment in Parkinson’s disease
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Although the neuropathology underlying cognitive impairments in PD broadly conforms to what is termed a ‘subcortical’ syndrome, there is considerable inter-patient heterogeneity.[Fields, 2017] This variation has led to the suggestion that patients with PD and cognitive impairments can be categorised into those with either frontostriatal, or posterior cortical, disruption.[Fields, 2017; Goldman & Litvan, 2011; Biundo et al., 2016; Williams-Gray et al., 2009] Interestingly, it has been suggested that the pathology underlying a patient’s cognitive impairment can predict the subsequent development of dementia.[Williams-Gray et al., 2009] The five-year ‘CamPaIGN’ cohort study observed that patients with ‘frontal–executive’ impairments (linked to COMT genotype and dopaminergic medication) are significantly less likely to develop dementia, whereas patients with ‘posterior–cortical’ impairments (linked to MAPT genotype and ageing) are more likely to develop dementia.[Williams-Gray et al., 2009] It is questionable, however, to what extent this distinction can be used to discriminate whether individual patients are likely to progress to developing dementia or not.[Biundo et al., 2016]

Conversely, it has also been argued that, despite the potential for stratification into distinct aetiologies, a single model for Lewy body cognitive abnormalities should be adopted, in order that research into the field be as useful and widely-applicable as possible.[Biundo et al., 2016]
 

Biundo R, Weis L, Antonini A. Cognitive decline in Parkinson’s disease: the complex picture. NPJ Parkinson’s Disease 2016; 2: 16018.

Fields JA. Cognitive and neuropsychiatric features in Parkinson’s and Lewy body dementias. Arch Clin Neuropsychol 2017; 32 (7): 786–801.

Goldman JG, Litvan I. Mild cognitive impairment in Parkinson’s disease. Minerva Med 2011; 102 (6): 441–459.

Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort. Brain 2009; 132 (Pt 11): 2958–2969.

Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007; 22 (12): 1689–1707.

Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society task force guidelines. Mov Disord 2012; 27 (3): 349–356.

Weil RS, Costantini AA, Schrag AE. Mild cognitive impairment in Parkinson’s disease – what is it? Curr Neurol Neurosci Rep 2018; 18 (4): 17.

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MDS diagnostic criteria for MCI in Parkinson’s disease
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The MDS diagnostic criteria for MCI in PD represent an attempt to harmonise the various definitions of MCI in PD that have been used in the past.[Litvan et al., 2012] A uniform definition allows identification of:[Litvan et al., 2012]

  • the clinical characteristics of the earliest stage of PD cognitive impairment
  • the best predictors of conversion from PD–MCI to PD dementia
  • the effects of PD–MCI on the quality of life and day-to-day functioning of patients with PD
  • a well-characterised patient population, and a potential outcome measure, for clinical trials
  • a useful clinical entity that will allow clinicians, patients, caregivers, and researchers to communicate better, thereby improving patient care and research efforts.

Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society task force guidelines. Mov Disord 2012; 27 (3): 349–356.

Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007; 22 (12): 1689–1707.

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Prevalence of MCI in patients with Parkinson’s disease
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One of the problems that researchers have when studying impaired cognition in PD is the wide variation in criteria used to define MCI, which can make comparisons between studies challenging.[Aarsland et al., 2010; Meireles & Massano, 2012]
One study managed to harmonise data from various cohorts by applying the MDS diagnostic criteria.[Aarsland et al., 2010] In doing so, it was possible to pool data from eight cohorts into a group large enough to explore MCI in subgroups based on age, sex, and duration and stage of PD.[Aarsland et al., 2010] MCI was associated with increasing age at the time of assessment and at disease onset, increasing duration of disease, severity of motor symptoms and disease stage, presence of depression, and lower proportion of dopamine agonist use.[Aarsland et al., 2010] Among the three cognitive domains (memory, attention/executive, visuospatial), memory impairment was the most common deficit (13.3%), followed by visuospatial impairment (11.0%) and then attention/executive function impairment (10.1%).[Aarsland et al., 2010] Impairment in only one of the three domains occurred in 19.5% of patients, while 5.4% had impairment in two domains, and 0.9% had impairment in all three domains.[Aarsland et al., 2010]

Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 2010; 75 (12): 1062–1069.

Meireles J, Massano J. Cognitive impairment and dementia in Parkinson’s disease: clinical features, diagnosis, and management. Front Neurol 2012; 3: 88.
 

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Diagnostic criteria for dementia in Parkinson’s disease
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While developing the new guidelines for diagnosis of dementia in PD, the MDS task force conducted a comprehensive and systematic review of studies in this area.[Emre et al., 2007] The task force examined every aspect of dementia that occurs over the course of PD, including its epidemiology; its effects on different aspects of cognition; its behavioural and psychiatric symptoms; and its relationship to motor and other non-motor symptoms.[Emre et al., 2007]

It should be noted that the more recent MDS–PD criteria do not consider dementia as an exclusion criterion for PD regardless of timing – ‘PD dementia with Lewy body subtype’.[Berg et al., 2014; Postuma et al., 2016]

Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson’s disease. Mov Disord 2014; 29 (4): 454–462.

Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007; 22 (12): 1689–1707.

Postuma RB, Berg D, Stern M, et al. Abolishing the 1-year rule: how much evidence will be enough? Mov Disord 2016; 31 (11): 1623–1627.

Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the Movement Disorder Society task force. Mov Disord 2007; 22 (16): 2314–2324. 

Poewe W, Gauthier S, Aarsland D, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract 2008; 62 (10): 1581–1587. 

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Management of cognitive symptoms in Parkinson’s disease
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The risk factors for PD dementia can be grouped into clinical, molecular, and structural/functional imaging risk factors – as depicted on slide.[Aarsland et al., 2017] 

Several potential therapies and interventions have been proposed or researched to tackle the cognitive symptoms of PD, and whilst there is now some good evidence that certain pharmacotherapies are effective in patients with PD and cognitive symptoms, more good-quality placebo-controlled trials are needed.[Aarsland et al., 2017; Weintraub & Mamikonyan, 2019; Seppi et al., 2019] A disease-modifying therapy that can slow the progression of PD, and delay the onset of dementia, is an urgent unmet need.[Aarsland et al., 2017; Chaudhuri et al., 2016]

Aarsland D, Creese B, Politis M, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol 2017; 13 (4): 217–231.

Chaudhuri KR, Bhidayasiri R, van Laar T. Unmet needs in Parkinson’s disease: new horizons in a changing landscape. Parkinsonism Relat Disord 2016; 33 (Suppl 1): S2–S8.

Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease – an evidence-based medicine review. Mov Disord 2019; 34 (2): 180–198.

Weintraub D, Mamikonyan E. The neuropsychiatry of Parkinson disease: a perfect storm. Am J Geriatr Psychiatry 2019; 27 (9): 998–1018.

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Quote
References

Lawson RA, Yarnall AJ, Duncan GW, et al. Severity of mild cognitive impairment in early Parkinson’s disease contributes to poorer quality of life. Parkinsonism Relat Disord 2014; 20 (10): 1071–1075.

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Mood disorders
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The spectrum of mood disorders in Parkinson’s disease
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Mood disorders have been associated with significant morbidity and mortality in patients with PD, and are a major determinant of quality of life.[Connolly & Fox, 2014] 

Depression, anxiety, and apathy are common in PD and may precede the appearance of motor symptoms in some patients.[Connolly & Fox, 2014; Schrag et al., 2015] The onset of depression and anxiety probably reflects changes to the production and effect of several key neurotransmitters.[Connolly & Fox, 2014] During later stages of PD, ‘OFF’ periods associated with low levels of dopamine in the brain can trigger anxiety, occasionally so severely as to induce panic attacks that require emergency care.[Connolly & Fox, 2014]

Apathy refers to a set of behavioural, emotional and cognitive features that involve reduced interest and motivation in goal-directed behaviours, indifference, and flattened mood.[Tan, 2012] Although these features are often experienced during clinical depression, they can also exist by themselves and may therefore be considered a distinct clinical entity.[Wen et al., 2016]

Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson’s disease. Neurotherapeutics 2014; 11 (1): 78–91.

Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 2015; 14 (1): 57–64.

Tan LC. Mood disorders in Parkinson’s disease. Parkinsonism Relat Disord 2012; 18 (Suppl 1): S74–S76.

Wen MC, Chan LL, Tan LC, Tan EK. Depression, anxiety, and apathy in Parkinson’s disease: insights from neuroimaging studies. Eur J Neurol 2016; 23 (6): 1001–1019.

Aarsland D, Påhlhagen S, Ballard CG, et al. Depression in Parkinson disease – epidemiology, mechanisms and management. Nat Rev Neurol 2011; 8 (1): 35–47. 

Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat Rev Neurosci 2017; 18 (7): 435–450.

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Depression in Parkinson’s disease
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Depression is highly prevalent in PD; 35% of patients with PD report clinically significant depressive symptoms, and 17% have major depressive disorder.[Reijnders et al., 2008] The symptoms of depression may often go unrecognised and, thus, untreated.[Connolly & Fox, 2014] The reduced facial expression (hypomimia) and general slowness of movement associated with bradykinesia may mask certain aspects of depression, complicating the diagnosis.[Connolly & Fox, 2014; Weiss & Pontone, 2019] Depression is a key determinant of reduced quality of life in patients with PD.[Tan, 2012] It is associated with sleep disturbances, fatigue, decreased functional ability, and reduced ability to perform activities of daily living.[Tan, 2012]

The underlying cause of PD-related depression can be difficult to identify.[Tan, 2012] In some cases, it may be a reactive state in which an individual struggles with their condition.[Tan, 2012] Depression may also occur as an intrinsic part of the neurodegenerative pathology of PD (perhaps explaining the high risk of depression prior to the onset of clinical motor symptoms).[Tan, 2012; Schrag et al., 2015]

Treatment of depression in PD is broadly similar to treatment of depression in people without PD.[Tan, 2012] This comprises a mixture of pharmacological therapies (e.g., selective serotonin reuptake inhibitors, serotonin–noradrenaline reuptake inhibitors, and tricyclic antidepressants)[Tan, 2012] and non-pharmacological therapies (e.g., patient support groups,[Tan, 2012] cognitive behavioural therapy,[Tan, 2012] mindfulness training,[Dissanayaka et al., 2016] and exercise[Reynolds et al., 2016]). Patients may also benefit from adjusting their dopaminergic medication, since depressive symptoms can be worse during periods of dopamine deficiency (‘OFF’ periods).[Connolly & Fox, 2014]
 
 

Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson’s disease. Neurotherapeutics 2014; 11 (1): 78–91.

Dissanayaka NNW, Jion FI, Pachana NA, et al. Mindfulness for motor and nonmotor dysfunctions in Parkinson’s disease. Parkinsons Dis 2016; 2016: 7109052.

Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord 2008; 23 (2): 183–189.

Reynolds GO, Otto MW, Ellis TD, et al. The therapeutic potential of exercise to improve mood, cognition, and sleep in Parkinson’s disease. Mov Disord 2016; 31 (1): 23–38.

Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 2015; 14 (1): 57–64.

Tan LC. Mood disorders in Parkinson’s disease. Parkinsonism Relat Disord 2012; 18 (Suppl 1): S74–S76.

Weiss HD, Pontone GM. “Pseudo-syndromes” associated with Parkinson disease, dementia, apathy, anxiety, and depression. Neurol Clin Pract 2019; 9 (4): 354–359.

Aarsland D, Påhlhagen S, Ballard CG, et al. Depression in Parkinson disease – epidemiology, mechanisms and management. Nat Rev Neurol 2011; 8 (1): 35–47.

Schrag A. Quality of life and depression in Parkinson’s disease. J Neurol Sci 2006; 248 (1–2): 151–157.

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Anxiety in Parkinson’s disease
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Anxiety is a common comorbidity in patients with PD and is likely to be underdiagnosed and undertreated.[Pontone et al., 2009] Anxiety may take several forms, including panic disorder, obsessive–compulsive disorder, generalised anxiety disorder (GAD), and social phobias, and often occurs alongside other mental health disorders, particularly depression.[Dissanayaka et al., 2010] In some cases, anxiety precedes the onset of motor symptoms.[Dissanayaka et al., 2010; Schrag et al., 2014] 

High levels of anxiety are associated with more severe motor symptoms, and reduced ability to perform activities of daily living.[Dissanayaka et al., 2010] However, the extent to which a loss of independence increases anxiety, or greater levels of anxiety results in a loss of independence, remains unclear.[Dissanayaka et al., 2010] It is certainly plausible that neurodegeneration in the brainstem during early PD may have mood-altering effects, including increased anxiety and panic disorders.[Tan, 2012]

Anxiety may be present almost continuously, or only during or either side of ‘OFF’ periods.[Connolly & Fox, 2014] The dose of levodopa does not appear to affect the likelihood of anxiety, although the presence of drug-related complications, such as dyskinesias and ON/OFF fluctuations, may be a factor.[Dissanayaka et al., 2010] Alterations to the drug regimen that reduce these side effects may therefore help to reduce anxiety.[Connolly & Fox, 2014]

There is currently no proven drug therapy for the treatment of anxiety in PD.[Connolly & Fox, 2014; Seppi et al., 2019] Common approaches to its management include the use of antidepressant medication, counselling, education-based strategies, and relaxation techniques.[Connolly & Fox, 2014] However, currently there is little evidence from clinical trials demonstrating the effectiveness of these interventions.[Connolly & Fox, 2014]

Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson’s disease. Neurotherapeutics 2014; 11 (1): 78–91.

Dissanayaka NN, Sellbach A, Matheson S, et al. Anxiety disorders in Parkinson’s disease: prevalence and risk factors. Mov Disord 2010; 25 (7): 838–845.

Pontone GM, Williams JR, Anderson KE, et al. Prevalence of anxiety disorders and anxiety subtypes in patients with Parkinson’s disease. Mov Disord 2009; 24 (9): 1333–1338. 

Tan LC. Mood disorders in Parkinson’s disease. Parkinsonism Relat Disord 2012; 18 (Suppl 1): S74–S76. 

Schrag A, Horsfall L, Walters K, et al. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 2015; 14 (1): 57–64.

Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease – an evidence-based medicine review. Mov Disord 2019; 34 (2): 180–198.

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Apathy in Parkinson’s disease
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References

Apathy refers to a set of behavioural, emotional and cognitive features that involve reduced interest and motivation in goal-directed behaviours, indifference, and flattened mood.[Tan, 2012; Pagonabarraga et al., 2015] Essentially, the individual lacks motivation and they appear to be emotionally numb.[Tan, 2012; Pagonabarraga et al., 2015] Apathy in patients with PD is associated with poor quality of life, impaired daily functioning, medication non-compliance, and increased mortality.[Barone et al., 2009; Connolly & Fox, 2014]

Apathy can often be a component of depression, but in PD it is not uncommon to find apathy in patients who do not suffer from depression.[APA, 2013] Apathy may also be one of the more frequent and distressing neuropsychiatric symptoms of PD for caregivers and next of kin.[Connolly & Fox, 2014]

Although clinically often challenging to manage, there is emerging evidence from clinical studies for pharmacological treatments including medications that enhance cholinergic and/or dopaminergic neurotransmission.[Seppi et al., 2019; Pagonabarraga et al., 2015] Some studies have reported that motivation is greater during ‘ON’ states when levodopa levels are at their most effective, suggesting that optimising dopaminergic medication may prove beneficial.[Connolly & Fox, 2014]
 

American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition. Arlington, VA: American Psychiatric Publishing, 2013.

Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 2009; 24 (11): 1641–1649.

Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson’s disease. Neurotherapeutics 2014; 11 (1): 78–91.

Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson’s disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 2015; 14 (5): 518–531.

Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson’s disease – an evidence-based medicine review. Mov Disord 2019; 34 (2): 180–198.

Tan LC. Mood disorders in Parkinson’s disease. Parkinsonism Relat Disord 2012; 18 (Suppl 1): S74–S76.Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord 2009; 24 (15): 2175–2186.

Dujardin K, Sockeel P, Delliaux M, et al. Apathy may herald cognitive decline and dementia in Parkinson’s disease. Mov Disord 2009; 24 (16): 2391–2397.

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Psychosis and Parkinson’s disease
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Psychosis and Parkinson’s disease
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Psychotic symptoms are a frequent feature of PD during its later stages, and can have a major effect on patient quality of life, as well as that of caregivers.[Samudra et al., 2016] Treatment of psychotic symptoms in patients with PD is complicated by their close relationship with dopaminergic medication.[Samudra et al., 2016; Goldman et al., 2014; Weintraub et al., 2019] Psychotic symptoms may be relieved by decreasing the doses or frequency of PD medications, but this may lead to an unacceptable worsening of motor symptoms, such as bradykinesia, tremor, and muscular rigidity.[Samudra et al., 2016; Goldman et al., 2014; Weintraub et al., 2019] Clinicians, therefore, often choose to use low-dose antipsychotic medications to relieve symptoms.[Samudra et al., 2016]

Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol 2014; 16 (3): 281. 

Samudra N, Patel N, Womack KB, et al. Psychosis in Parkinson disease: a review of etiology, phenomenology, and management. Drugs Aging 2016; 33 (12): 855–863.

Weintraub D, Mamikonyan E. The neuropsychiatry of Parkinson disease: a perfect storm. Am J Geriatr Psychiatry 2019; 27 (9): 998–1018.

Fénelon G, Alves G. Epidemiology of psychosis in Parkinson’s disease. J Neurol Sci 2010; 289 (1–2): 12–17.

Friedman JH. Parkinson disease psychosis: update. Behav Neurol 2013; 27 (4): 469–477. 

Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri KR. Management of psychosis in Parkinson’s disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinsons Dis 2017; 2017: 3256542.

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The prevalence of psychosis in patients with Parkinson’s disease
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Visual hallucinations appear to be the most common psychotic symptom in PD; estimates suggest that 16–38% of patients experience them at some point.[Chang & Fox, 2016] Auditory hallucinations are less common (0–22%) and usually occur alongside visual hallucinations.[Chang & Fox, 2016] 

Delusions are least common (1–7%), but occur more often in patients with dementia.[Chang & Fox, 2016] They are probably the most significant and disabling of all the psychotic symptoms.[Chang & Fox, 2016] Often paranoid in nature, delusions may cause great distress to the patient and their caregivers.[Friedman, 2013] 

A study that assessed patients with PD after 12 years of follow-up found that 60% had evidence of hallucinations or delusions.[Forsaa et al., 2010] Those most likely to develop psychotic symptoms later during the disease were patients who:[Forsaa et al., 2010] 

  • were older at the onset of motor symptoms
  • had a higher initial levodopa dose
  • who had been suffering from REM sleep behaviour disorder (RBD).
     

Chang A, Fox SH. Psychosis in Parkinson’s disease: epidemiology, pathophysiology, and management. Drugs 2016; 76 (11): 1093–1118. 

Forsaa EB, Larsen JP, Wentzel-Larsen T, et al. A 12-year population-based study of psychosis in Parkinson disease. Arch Neurol 2010; 67 (8): 996–1001. 

Friedman JH. Parkinson disease psychosis: update. Behav Neurol 2013; 27 (4): 469–477. 

Mack J, Rabins P, Anderson K, et al. Prevalence of psychotic symptoms in a community-based Parkinson disease sample. Am J Geriatr Psychiatry 2012; 20 (2): 123–132.

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The conflict of treating psychosis in Parkinson’s disease
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One of the main challenges of treating psychotic symptoms in PD is that many antipsychotic medications have an anti-dopaminergic effect, i.e., they block the action of dopamine.[Divac et al., 2016] In doing so, antipsychotics counteract the action of levodopa and can worsen the control of motor symptoms.[Divac et al., 2016] Patients are therefore caught ‘between a rock and a hard place’, feeling unable to take antipsychotic medications without incurring a worsening of physical symptoms.[Divac et al., 2016] Newer drugs can be effective in treating psychotic symptoms, but with a less potent dopamine-blocking action.[Divac et al., 2016] These are sometimes referred to as ‘atypical antipsychotics’.[Samudra et al., 2016]

The symptoms of psychosis are thought to be more complex than aberrant dopamine signalling.[Rolland et al., 2014] In patients with PD, there is evidence for acetylcholine and serotonin signalling, as well as dopamine neurotransmission, being involved in the pathophysiology of psychosis.[Samudra et al., 2016]
 

Divac N, Stojanović R, Savić Vujović K, et al. The efficacy and safety of antipsychotic medications in the treatment of psychosis in patients with Parkinson’s disease. Behav Neurol 2016; 2016: 4938154.

Samudra N, Patel N, Womack KB, et al. Psychosis in Parkinson disease: a review of etiology, phenomenology, and management. Drugs Aging 2016; 33 (12): 855–863.

Rolland B, Jardri R, Amad A, et al. Pharmacology of hallucinations: several mechanisms for one single symptom? Biomed Res Int 2014; 2014: 307106.

Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134.

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Other important non-motor symptoms
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Gastrointestinal symptoms
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Gastrointestinal (GI) symptoms are commonly experienced by patients with PD, particularly difficulties with swallowing (dysphagia), drooling, and constipation.[Fasano et al., 2015] 

Drooling, where saliva is involuntarily lost from the mouth, is an embarrassing problem with a severe impact on social functioning.[Kalf et al., 2009] It affects approximately half of all patients with PD, but may be managed with the use of behavioural techniques, and with training from a speech therapist who will help the patient to swallow.[Kalf et al., 2009] 

Constipation is often evident several years, or even decades, prior to the onset of motor symptoms.[Fasano et al., 2015] The pathological mechanisms behind constipation in PD remain unclear, however, although there is some evidence of greater α-synuclein accumulation in the colons of patients with PD.[Lebouvier et al., 2008] Some medications used to treat PD, particularly anticholinergics and dopamine agonists, may increase the likelihood of suffering from constipation, but there is also likely to be a loss of GI function caused by the disease process itself.[Fasano et al., 2015; Mukherjee et al., 2016]

Standard treatment options include: a high-fibre diet (including psyllium supplements), increased fluid intake, the use of laxatives, and neuromuscular training in the form of ‘biofeedback therapy’.[Fasano et al., 2015; Mukherjee et al., 2016]

Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015; 14 (6): 625–639.

Kalf JG, de Swart BJ, Borm GF, et al. Prevalence and definition of drooling in Parkinson’s disease: a systematic review. J Neurol 2009; 256 (9): 1391–1396.

Lebouvier T, Chaumette T, Damier P, et al. Pathological lesions in colonic biopsies during Parkinson’s disease. Gut 2008; 57: 1741–1743.

Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson’s disease. World J Gastroenterol 2016; 22 (25): 5742–5752.

Barboza JL, Okun MS, Moshiree B. The treatment of gastroparesis, constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson’s disease. Expert Opin Pharmacother 2015; 16 (16): 2449–2464.

Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated with Parkinson disease: an RCT. Neurology 2016; 87 (12): 1274–1280.

Lubomski M, Tan AH, Lim SY, et al. Parkinson’s disease and the gastrointestinal microbiome. J Neurol 2019. [Epub].

Palma JA, Kaufmann H. Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Mov Disord 2018; 33 (3): 372–390.

Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol 2018; 20 (12): 54. 

Scheperjans F. Gut microbiota, 1013 new pieces in the Parkinson’s disease puzzle. Curr Opin Neurol 2016; 29 (6): 773–780.

Todorova A, Jenner P, Ray Chaudhuri K. Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract Neurol 2014; 14 (5): 310–322.
 

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Speech problems
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References

At first, problems with speech may not be noticeable to the affected individual but, as the disease progresses, they may become more difficult to understand as their words become slurred or slow.[Tjaden, 2008] The pitch and loudness of the voice become more monotonous, and generally quieter than usual (hypophonia).[Tjaden, 2008] Sentences may be cut short by inappropriate silences, and the pace of words is either too rushed or too slow, compared to normal.[Tjaden, 2008] Occasionally, the tone of the voice itself may change, becoming more nasal, harsh, or breathy.[Tjaden, 2008]

The communication problems faced by patients with PD often run deeper than speech; patients can also experience problems with word retrieval.[Saldert & Bauer, 2017] One qualitative analysis highlighted the multifaceted nature of the communication problems that patients with PD face in everyday conversations.[Saldert & Bauer, 2017] Examples include patients failing to communicate the essential information of a sentence, mixing up words, and using atypical words or phrases.[Saldert & Bauer, 2017]

Saldert C, Bauer M. Multifaceted communication problems in everyday conversations involving people with Parkinson’s disease. Brain Sci 2017; 7 (10).

Tjaden K. Speech and swallowing in Parkinson’s disease. Top Geriatr Rehabil 2008; 24 (2): 115–126.

Dorland WAN. Dorland’s Illustrated Medical Dictionary. 31st edition. Philadelphia, PA: Saunders, 2007.

Ramig L, Halpern A, Spielman J, et al. Speech treatment in Parkinson’s disease: randomized controlled trial (RCT). Mov Disord 2018; 33 (11): 1777–1791.

Schalling E, Johansson K, Hartelius L. Speech and communication changes reported by people with Parkinson’s disease. Folia Phoniatr Logop 2017; 69 (3): 131–141.

Tamplin J, Morris ME, Marigliani C, et al. ParkinSong: a controlled trial of singing-based therapy for Parkinson’s disease. Neurorehabil Neural Repair 2019; 33 (6): 453–463.

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Swallowing problems (dysphagia)
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References

Problems with the swallowing of foods, liquids or saliva (dysphagia) may occur at any stage of PD and affect 40–95% of patients.[Tjaden, 2008] This can have serious consequences, particularly if foods or liquids are taken into the respiratory tract (aspiration) where they can cause infections, such as pneumonia.[Fasano et al., 2015] 

Dysphagia also increases the risk of dehydration and malnutrition.[Tjaden, 2008] The time, effort, and difficulty associated with chewing and swallowing may discourage patients from consuming sufficient food and water, resulting in an inadequate intake of water, energy, and nutrients.[Tjaden, 2008] 

Loss of saliva through excessive drooling can lead to a dry mouth (xerostomia) and difficulty in forming a moist bolus of food, which can be uncomfortable when the patient tries to swallow.[Tjaden, 2008] 

Dysphagia in PD is complex and highly variable in nature and severity.[Tjaden, 2008] This can make clinical assessment challenging and sometimes unreliable.[Suttrup & Warnecke, 2016]

Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015; 14 (6): 625–639.

Suttrup I, Warnecke T. Dysphagia in Parkinson’s disease. Dysphagia 2016; 31 (1): 24–32.

Tjaden K. Speech and swallowing in Parkinson’s disease. Top Geriatr Rehabil 2008; 24 (2): 115–126.

Dziewas R, Beck AM, Clave P, et al. Recognizing the importance of dysphagia: stumbling blocks and stepping stones in the twenty-first century. Dysphagia 2017; 32 (1): 78–82.

Kwon M, Lee JH. Oro-pharyngeal dysphagia in Parkinson’s disease and related movement disorders. J Mov Disord 2019; 12 (3): 152–160.

Martin EA (ed). Concise Colour Medical Dictionary, 4th edition. Oxford: Oxford University Press, 2007.
 

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Sleep disturbances
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References

Sleep disturbances are amongst the most troublesome of the non-motor symptoms of PD, affecting 60–90% of patients at some point in the disease course.[Maass & Reichmann, 2013] Sleep disturbances can take the form of insomnia, excessive daytime sleepiness, restless legs syndrome (where the patient has an urge to move), and rapid eye movement (REM) sleep behaviour disorder (RBD).[Lima, 2013]

RBD is a characteristic feature of PD and may precede the onset of motor symptoms by many years.[St. Louis et al., 2017; Zhang et al., 2017] It is present in approximately 25–50% of patients with PD,[Lima, 2013; Maas & Reichmann 2013] and involves the loss of normal atonia (muscle paralysis) of REM sleep, resulting in an apparent acting out of dreams.[St. Louis et al., 2017] The presence of RBD in prodromal PD may be caused by the underlying Lewy pathology in the lower brainstem, which tends to occur before the pathology moves up into the substantia nigra.[St. Louis et al., 2017; Zhang et al., 2017]

Sleep disorders can be managed with a combination of behavioural and pharmacological therapies, including a reduction in stimulant intake, better sleep hygiene, adjustment of the sleeping environment to prevent injury of patients with RBD, greater levels of physical activity, and certain drug therapies.[Cusso et al., 2016; Todorova et al., 2014] 

Cusso ME, Donald KJ, Khoo TK. The impact of physical activity on non-motor symptoms in Parkinson’s disease: a systematic review. Front Med (Lausanne) 2016; 3: 35.

Lima MM. Sleep disturbances in Parkinson’s disease: the contribution of dopamine in REM sleep regulation. Sleep Med Rev 2013; 17 (5): 367–375.

Maass A, Reichmann H. Sleep and non-motor symptoms in Parkinson’s disease. J Neural Transm (Vienna) 2013; 120 (4): 565–569.

St Louis EK, Boeve AR, Boeve BF. REM sleep behavior disorder in Parkinson’s disease and other synucleinopathies. Mov Disord 2017; 32 (5): 645–658. 

Todorova A, Jenner P, Ray Chaudhuri K. Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract Neurol 2014; 14 (5): 310–322.

Zhang J, Xu CY, Liu J. Meta-analysis on the prevalence of REM sleep behaviour disorder symptoms in Parkinson’s disease. BMC Neurol 2017; 17 (1): 23.

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Pain
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References

Pain is defined as an unpleasant or distressing sensory experience.[NCCCC, 2006] It occurs in a large proportion of cases of PD, but in individual patients it is often difficult to determine whether the pain is due to the PD itself.[Silverdale et al., 2018; NCCCC, 2006; Young Blood et al., 2016]

The most common form of pain in PD is musculoskeletal, which typically occurs as a result of muscle rigidity and hypokinesia (e.g., frozen shoulder).[NCCCC, 2006] This kind of pain usually occurs on the side on which motor symptoms first appeared or are more severe.[Young Blood et al., 2016] It can be associated with the presence and severity of motor symptoms, meaning the pain may be reduced when dopaminergic therapy is optimised.[Young Blood et al., 2016] Musculoskeletal pain is most common in the lower back and legs, although shoulder pain is also quite common during the early stages of the disease.[Young Blood et al., 2016]
Dystonic pain is a result of abnormal postures brought on by ‘OFF’ periods.[Young Blood et al., 2016] It is characterised by sustained or intermittent muscle contractions that result in abnormal, frequently repetitive movements and/or postures.[Young Blood et al., 2016] These contractions cause intense pain, often in the feet.[NCCCC, 2006]

Pain often presents with other non-motor symptoms, including depression, and the two can be mutually reinforcing.[Young Blood et al., 2016] Successful treatment of depression may therefore improve the perception and processing of pain in the mind of the patient.[Young Blood et al., 2016]
 

National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.

Silverdale MA, Kobylecki C, Kass-Iliyya, et al. A detailed clinical study of pain in 1957 participants with early/moderate Parkinson’s disease. Parkinsonism Relat Disord 2018; 56: 27–32. 

Young Blood MR, Ferro MM, Munhoz RP, et al. Classification and characteristics of pain associated with Parkinson’s disease. Parkinsons Dis 2016; 2016: 6067132.

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Neurogenic orthostatic hypotension
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Postural/orthostatic hypotension
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References

Postural, or ‘orthostatic’, hypotension is a common and sometimes disabling cardiovascular symptom of PD, affecting >30% of patients with PD.[Sánchez-Ferro et al., 2013] It is characterised by a sustained reduction of systolic blood pressure of at least 20 mmHg, or diastolic blood pressure of 10 mmHg, within three minutes of standing or head-up tilt to at least 60° on a tilt table.[Freeman et al., 2011]

Postural hypotension may cause serious morbidity and mortality, particularly when it results in the patient falling.[Sánchez-Ferro et al., 2013] Many of the commonly prescribed medications used for PD may increase the frequency of postural hypotension and, for this reason, it may be prudent to monitor blood pressure after the introduction of a new drug to the treatment regimen or an alteration in dose.[Sánchez-Ferro et al., 2013]

Non-pharmacological interventions are generally the first form of therapy used to reduce postural hypotension, because they are least likely to have side effects or adverse outcomes.[Sánchez-Ferro et al., 2013] One of the simplest and most common interventions is increased fluid and salt intake, which has been shown in other autonomic disorders to be effective in combatting postural hypotension, although not in PD itself.[Sánchez-Ferro et al., 2013]

A patient suffering from postural hypotension can also learn physical countermeasures that will promote return of blood flow and maintain cardiac output.[Sánchez-Ferro et al., 2013] These include tiptoeing, leg crossing, bending forward, and squatting.[Sánchez-Ferro et al., 2013]

Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011; 21 (2): 69–72.

Sánchez-Ferro A, Benito-León J, Gómez-Esteban JC. The management of orthostatic hypotension in Parkinson’s disease. Front Neurol 2013; 4: 64.

Espay AJ, LeWitt PA, Hauser RA, et al. Neurogenic orthostatic hypotension and supine hypertension in Parkinson’s disease and related synucleinopathies: prioritisation of treatment targets. Lancet Neurol 2016; 15 (9): 954–966.

Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med 2008; 358 (6): 615–624. 

Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017; 264 (8): 1567–1582.

Kaufmann H, Norcliffe-Kaufmann L, Palma JA. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther 2015; 13 (8): 875–891.

Martin EA (ed). Concise Colour Medical Dictionary, 4th edition. Oxford: Oxford University Press, 2007.

Todorova A, Jenner P, Ray Chaudhuri K. Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract Neurol 2014; 14 (5): 310–322.

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Symptoms of orthostatic hypotension
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References

Damage to the autonomic nervous system can result in a failure of blood pressure regulation.[Kaufmann et al., 2015] The autonomic nervous system, using noradrenaline signalling, would normally regulate blood pressure from dropping more than a modest amount (10 mmHg systolic blood pressure) upon standing.[Metzler et al., 2013; Palma & Kaufmann, 2017; Gibbons et al., 2017] These sympathetic systems can become damaged in diseases such as PD and, when they are dysfunctional, this can lead to orthostatic hypotension of neurogenic cause.[Kaufmann et al., 2015; Metzler et al., 2013]

The symptoms of neurogenic orthostatic hypotension, as shown on the slide, vary from patient to patient, but classically include dizziness, lightheadedness, and feeling close to fainting.[Kaufmann et al., 2015]

Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017; 264 (8): 1567–1582.

Kaufmann H, Norcliffe-Kaufmann L, Palma JA. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther 2015; 13 (8): 875–891.

Metzler M, Duerr S, Granata R, et al. Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol 2013; 260 (9): 2212–2219.

Palma JA, Kaufmann H. Epidemiology, diagnosis, and management of neurogenic orthostatic hypotension. Mov Disord Clin Pract 2017; 4 (3): 298–308. 

Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 2011; 21 (2): 69–72.

Freeman R. Neurogenic orthostatic hypotension. N Engl J Med 2008; 358 (6): 615–624.

Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation 2009; 119 (1): 139–146.

Mathias CJ. L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience. Clin Auton Res 2008; 18 (Suppl 1): 25–29.

Perlmuter LC, Sarda G, Casavant V, et al. A review of orthostatic blood pressure regulation and its association with mood and cognition. Clin Auton Res 2012; 22 (2): 99–107. 

Sclater A, Alagiakrishnan K. Orthostatic hypotension: a primary care primer for assessment and treatment. Geriatrics 2004; 59 (8): 22–27.

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Patient impact of neurogenic orthostatic hypotension
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References

One study investigated the patient impact of neurogenic orthostatic hypotension (nOH) by surveying 363 patients, 90% of whom had PD, and 128 of their caregivers.[Claassen et al., 2018] The survey included questions about the sorts of symptoms experienced, the timing of the symptoms, the impact of the symptoms, and the limitations that symptoms placed on the patient.[Claassen et al., 2018] The results showed the impact that nOH has on patients’ functioning and quality of life, including impaired mobility (such as difficulty with positional changes), increased frequency of falls, and decreased ability to maintain activities of daily life.[Claassen et al., 2018]

Claassen DO, Adler CH, Hewitt LA, Gibbons C. Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers. BMC Neurol 2018; 18 (1): 125.

oylan LS, Messinis L. Orthostatic hypotension, cognition, and Parkinson disease: dumbing down by standing up. Neurology 2017; 88 (1): 11–12.

Centi J, Freeman R, Gibbons CH, et al. Effects of orthostatic hypotension on cognition in Parkinson disease. Neurology 2017; 88 (1): 17–24.

Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation 2009; 119 (1): 139–146.

Mak MK, Pang MY. Fear of falling is independently associated with recurrent falls in patients with Parkinson’s disease: a 1-year prospective study. J Neurol 2009; 256 (10): 1689–1695. 

Maule S, Milazzo V, Maule MM, et al. Mortality and prognosis in patients with neurogenic orthostatic hypotension. Funct Neurol 2012; 27 (2): 101–106.

Merola A, Romagnolo A, Rosso M, et al. Orthostatic hypotension in Parkinson’s disease: does it matter if asymptomatic? Parkinsonism Relat Disord 2016; 33: 65–71.

Palma JA, Kaufmann H. Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies. Mov Disord 2018; 33 (3): 372–390. 

Perlmuter LC, Sarda G, Casavant V, et al. A review of orthostatic blood pressure regulation and its association with mood and cognition. Clin Auton Res 2012; 22 (2): 99–107.

Sclater A, Alagiakrishnan K. Orthostatic hypotension: a primary care primer for assessment and treatment. Geriatrics 2004; 59 (8): 22–27.

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Falls and fear of falling in patients with Parkinson’s disease
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References

One systematic review of falls in patients with PD, including 22 studies, showed that falls are common in patients with PD, as shown on the slide.[Allen et al., 2013] Furthermore, the rate of falls per recurrent faller was high, ranging from 4.7 to 67.6 falls per year – with one individual patient reporting falling more than 500 times in a 20-week period.[Allen et al., 2013] Factors associated with greater risk of falling included previous falling, and PD severity.[Allen et al., 2013] The authors highlight the need for the fear of falling to be assessed in patients with PD, given the inconsistent relationship that they found in the data between fear of falling and actual falling.[Allen et al., 2013] Where these two risks are connected, strategies to reduce fear of falling might be considered.[Allen et al., 2013]

Fear of falling can be a consequence of falling in elderly individuals.[Vellas et al., 1997] In one study, fear of falling was associated with female sex, older age, balance and gait abnormalities, and poor self-assessed physical health, cognitive health, and economic resources.[Vellas et al., 1997] Indeed, a fear of falling might well be a rational response to an individual making an assessment about their personal risk of falling, particularly among frail, elderly women.[Vellas et al., 1997]

Allen NE, Schwarzel AK, Canning CG. Recurrent falls in Parkinson’s disease: a systematic review. Parkinsons Dis 2013; 2013: 906274.

Vellas BJ, Wayne SJ, Romero LJ, et al. Fear of falling and restriction of mobility in elderly fallers. Age Ageing 1997; 26 (3): 189–193.

Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation 2009; 119 (1): 139–146.

Jonasson SB, Nilsson MH, Lexell J, Carlsson G. Experiences of fear of falling in persons with Parkinson’s disease – a qualitative study. BMC Geriatr 2018; 18 (1): 44.

Lubomski M, Rushworth RL, Tisch S. Hospitalisation and comorbidities in Parkinson’s disease: a large Australian retrospective study. J Neurol Neurosurg Psychiatry 2015; 86 (3): 324–330.

Merola A, Romagnolo A, Rosso M, et al. Orthostatic hypotension in Parkinson’s disease: does it matter if asymptomatic? Parkinsonism Relat Disord 2016; 33: 65–71.

Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home residents. Am J Med 2000; 108 (2): 106–111. 

Pathak A, Lapeyre-Mestre M, Montastruc JL, Senard JM. Heat-related morbidity in patients with orthostatic hypotension and primary autonomic failure. Mov Disord 2005; 20 (9): 1213–1219.

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Diagnosis of neurogenic orthostatic hypotension
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References

The diagnosis of nOH involves ruling-out identifiable causes, such as other health conditions or the effect of medication, and then investigating the nOH.[Maule et al., 2007; Goldenstein & Sharabi, 2009] Further to the pathway outlined on the slide, nOH can be stratified based on evidence of central neurodegeneration, and certain neuroimaging tests and neuropharmacological probes – potentially distinguishing between multiple system atrophy, autoimmune autonomic ganglionopathy, pure autonomic failure, or PD.[Goldenstein & Sharabi, 2009]

Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation 2009; 119 (1): 139–146.

Maule S, Papotti G, Naso D, et al. Orthostatic hypotension: evaluation and treatment. Cardiovasc Hematol Disord Drug Targets 2007; 7 (1): 63–70.

Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017; 264 (8): 1567–1582.

Grubb BP. Neurocardiogenic syncope and related disorders of orthostatic intolerance. Circulation 2005; 111 (22): 2997–3006.

Norcliffe-Kaufmann L, Kaufmann H, Palma JA, et al. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol 2018; 83 (3): 522–531.

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Management of neurogenic orthostatic hypotension
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References

In treating patients with neurogenic orthostatic hypotension (nOH), the goal is to lessen the symptom burden, rather than attempting to achieve normal blood pressure on standing.[Maule et al., 2007; Palma & Kaufmann, 2017] The stepwise management of nOH involves:[Palma & Kaufmann, 2017] 

Removing aggravating factors – hypotensive drugs should be discontinued or the dose reduced, and anaemia should be investigated (anaemia can potentially worsen OH, by reducing the oxygen carrying potential of the blood).
Non-pharmacological treatments – there are many changes that can be encouraged before pharmacological treatments are considered. Patients should understand the effect of posture on blood pressure, and should learn the various physical countermeasures that can raise blood pressure.

Pharmacological treatments – if required, the pharmacological approach to treating nOH involves one or both of two strategies: expanding the intravascular volume, and increasing peripheral vascular resistance. The selection of either, or both, approaches depends on the individual needs and clinical background of the patient.

Palma JA, Kaufmann H. Epidemiology, diagnosis, and management of neurogenic orthostatic hypotension. Mov Disord Clin Pract 2017; 4 (3): 298–308. 

Maule S, Papotti G, Naso D, et al. Orthostatic hypotension: evaluation and treatment. Cardiovasc Hematol Disord Drug Targets 2007; 7 (1): 63–70.

Claassen DO, Adler CH, Hewitt LA, Gibbons C. Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers. BMC Neurol 2018; 18 (1): 125.

Freeman R. Neurogenic orthostatic hypotension. N Engl J Med 2008; 358 (6): 615–624. 

Isaacson SH. Managed care approach to the treatment of neurogenic orthostatic hypotension. Am J Manag Care 2015; 21 (13 Suppl): S258–268.

Kaufmann H, Norcliffe-Kaufmann L, Palma JA. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther 2015; 13 (8): 875–891.

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Comorbidities of PD
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The comorbidities of PD
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References

This study analysed a registry database of the state of Nebraska, USA, to explore the causes of hospitalisation in patients with PD between 2004–2012.[Xu et al., 2018] In total, 3,852 patients with PD were included in the study, and a comparison group of 19,260 control individuals was constructed.[Xu et al., 2018]

The analysis revealed that whilst some conditions were clearly more prevalent among patients with PD, there were other conditions that were less prevalent.[Xu et al., 2018] Hospitalised patients with PD were at a higher risk of dementia and other cognitive disorders, mood disorders, gastrointestinal disorders, and urinary tract infections.[Xu et al., 2018] Patients with PD appeared to be at a lower risk of developing cardiac dysrhythmias, disorders of lipid metabolism, coronary atherosclerosis, and diabetes.[Xu et al., 2018]

Xu K, Alnaji N, Zhao J, et al. Comorbid conditions in Parkinson’s disease: a population-based study of statewide Parkinson’s disease registry. Neuroepidemiology 2018; 50 (1–2): 7–17.

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Quote
References

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

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