Product information and disease description Place of product in therapy Disease description

Long-term morbidity

9 evidence topics · 9 sources

Dementia, dependency, and nursing home placement at 15 and 20 years

“One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicentre Study of Parkinson’s disease have survived.” (opens the source at this quote in a new tab)
“The average follow-up for the 52 surviving patients was 15.2 years (SD = 0.7 years); mean prestudy disease duration 23.5 months.” (opens the source at this quote in a new tab)
“Their average age at presentation was 56 years (SD = 7.9 years) compared to 62 years for the total initial group and their average age at follow-up was 71 years (SD = 7.9; range, 55–86 years).” (opens the source at this quote in a new tab)
“Falls occur in 81% of patients, and 23% sustained fractures.” (opens the source at this quote in a new tab)
“Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia.” (opens the source at this quote in a new tab)
“The mean score of the MMSE was 22.5 (SD = 8.3).” (opens the source at this quote in a new tab)
“Of 46 patients, 22 tested scored ≥ 26 of 30, and 11 of 46 patients scored <20.” (opens the source at this quote in a new tab)
“No patient is still employed, and 40% of patients live in aged care facilities.” (opens the source at this quote in a new tab)
“A total of 30 (58%) were deemed unable to live alone due to physical and/or cognitive disabilities” (opens the source at this quote in a new tab)
“Forty-two patients (81%) had fallen due to their Parkinson’s disease with a mean onset of 11.5 years (SD = 2.8).” (opens the source at this quote in a new tab)
“A total of 7 people had fractured their femur neck, 1 a humerus, 1 her jaw, and 4 various other bones due to falling.” (opens the source at this quote in a new tab)
“A striking finding in this study was that 48% of our patients who survived 15 years were demented; this rate compares to a prevalence of 4.8% to 11% in general population studies of people of similar age” (opens the source at this quote in a new tab)
“The GDS was fully administered to 41 patients: the mean score was 11.7 of 30 (SD = 5.7).” (opens the source at this quote in a new tab)
“There were 19 patients who scored <11 (not depressed), 19 who scored 11 to 20 (mildly depressed), and 3 people scored >20 (definite depression).” (opens the source at this quote in a new tab)
“Formed visual hallucinations were reported at some time by 26 of 52 (50%) by 15 years.” (opens the source at this quote in a new tab)
“The mean time to onset of hallucinations was 10.7 years (SD = 4.0).” (opens the source at this quote in a new tab)
“Orthostatic hypotension (OR, 2.49; 95% CI, 1.08–5.78) remained as the significant factor associated with hallucinations multivariately.” (opens the source at this quote in a new tab)
“Only 7 of 136 (5%) continued to follow a less troublesome course without severe fluctuations, significant imbalance, or dementia.” (opens the source at this quote in a new tab)

“Thirty patients (15 men and 15 women) have survived to be included in the 20-year follow-up that ranged from 19.8 to 22 years.” (opens the source at this quote in a new tab)
“Their average age is now 74 years (SD = 7.9), and was 54 years at presentation compared to 62 years for the initial total group.” (opens the source at this quote in a new tab)
“Dementia is present in 83% of 20-year survivors.” (opens the source at this quote in a new tab)
“Only one person lives independently and 48% are in nursing homes.” (opens the source at this quote in a new tab)
“At 20 years, the mean Hoehn and Yahr stage ‘‘on’’ was 4.2 and ‘‘off’’ was 4.6.” (opens the source at this quote in a new tab)
“Patients lived there for a mean of 34 months (SD = 27) before death.” (opens the source at this quote in a new tab)
“The mean activities of daily living score (UPDRS items 5–17) ‘‘on’’ was 19 (SD = 8) and ‘‘off’’ was 27 (SD = 8).” (opens the source at this quote in a new tab)
“Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%.” (opens the source at this quote in a new tab)
“Another 70 patients were demented before they died prior to 20 years, giving a total of 97 (75%) demented predeath.” (opens the source at this quote in a new tab)
“Urinary incontinence occurred in 22 (71%), fecal incontinence in 5 (17%), and constipation requiring daily laxatives was present in 12 (40%).” (opens the source at this quote in a new tab)
“Of the original cohort, 78 were known to have suffered visual hallucinations prior to death” (opens the source at this quote in a new tab)
“In this group, only 14/30 (47%) still see their neurologist after 20 years.” (opens the source at this quote in a new tab)

Clinical Dementia Rating at 20 years	Participants examined	Mean age at 20 years	Mean MMSE	Constructional apraxia (%)
0 to 0.5	“5”	“64”	“29”	“0”
1	“15”	“75”	“25”	“80”
2	“5”	“76”	“14”	“100”
3	“5”	“79”	“2”	“100”

Motor complications and levodopa-unresponsive disability at 15 and 20 years

“Although approximately 95% have experienced L-dopa–induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling.” (opens the source at this quote in a new tab)
“Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added.” (opens the source at this quote in a new tab)
“The average dose of L-dopa for 49 patients was 734 mg per day (SD = 481) taken on average 4.4 times per day (SD = 2.0).” (opens the source at this quote in a new tab)
“By 15 years, 49 of 52 (94%) had experienced dyskinesia.” (opens the source at this quote in a new tab)
“In this group of survivors, the mean duration of treatment before the onset of dyskinesia was 5.3 years (SD = 3.6): 4.2 years (SD = 2.9) for the L-dopa group and 6.9 years (SD = 4.0) for the bromocriptine group, a significant difference (t test, P = 0.009).” (opens the source at this quote in a new tab)
“Thus, 6 of 52 (12%) had experienced severe dyskinesia by 15 years.” (opens the source at this quote in a new tab)
“Conversely, 28 of 52 (54%) did not consider their dyskinesia disabling.” (opens the source at this quote in a new tab)
“End of dose failure was reported by 50 of 52 (96%) patients.” (opens the source at this quote in a new tab)
“Mean duration of L-dopa treatment was 6.2 years (SD = 3.6) before the onset of end of dose failure: 5.8 years for the L-dopa group and 6.6 years for the bromocriptine group (t test, P = 0.36, not significant)” (opens the source at this quote in a new tab)
“Predictable offs occurred in 44 of 52 (85%), unpredictable offs in 18 of 52 (35%), and sudden offs in 12 of 52 (23%).” (opens the source at this quote in a new tab)
“Offs occupied ≤ 25% of the day in 36 of 52 (69%), and 25 to 50% of the day in 7 of 52 (13%).” (opens the source at this quote in a new tab)
“Nine patients were considered off for ≥ 75% of the day.” (opens the source at this quote in a new tab)
“All were demented: Stage 4 to 5 on low doses of L-dopa (mean 311 mg/day) or on no L-dopa (3).” (opens the source at this quote in a new tab)
“Dystonia, particularly involving the feet in the early morning had occurred in 29 of 52 (56%), mean onset being 4.1 years (SD = 3.4).” (opens the source at this quote in a new tab)
“The mean onset time for the bromocriptine group was 6.0 years (SD = 1.7), but it was significantly earlier at 2.4 years (SD =1.7, t test, P = 0.002) for the L-dopa group.” (opens the source at this quote in a new tab)
“The major causes of disability in patients surviving for 15 or more years are falls, autonomic disturbance, neuropsychiatric symptoms, and dementia, aspects of the disease that are not improved by L-dopa.” (opens the source at this quote in a new tab)
“Motor fluctuations and dyskinesia are common but are a less disabling aspect of the disease in the majority.” (opens the source at this quote in a new tab)

“Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease.” (opens the source at this quote in a new tab)
“The mean levodopa intake is 729 mg/day (SD = 453) with a daily average of 4.7 intakes at 20 years.” (opens the source at this quote in a new tab)
“All of those on at least 300 mg of levodopa per day had experienced end of dose failure and dyskinesia.” (opens the source at this quote in a new tab)
“At 20 years, dyskinesia was graded as mild to moderate (UPDRS 1–2) for both duration and severity in all, but 3 patients where it was graded as 3.” (opens the source at this quote in a new tab)
“Sudden ‘‘offs’’ were reported by 5 of 30 and an equal number lacked a good ‘‘on’’ due to inadequate levodopa dosage because of dementia.” (opens the source at this quote in a new tab)
“All others were on for more than half the day.” (opens the source at this quote in a new tab)

Dementia and functional dependency in population-based incidence cohorts

“Median time to functional dependency was 7.4 years (95% CI 6.4–7.5) and the 10‐year probability was 70.7% (95% CI 65.5–75.7)” (opens the source at this quote in a new tab)
“The 10‐year dementia probability was 49.6% (95% CI 44.6–54.8)” (opens the source at this quote in a new tab)
“We demonstrate that poor outcomes in PD are common and often occur early (eg, about 10% had postural instability and dependency at diagnosis and over 25% developed dementia within 5 years).” (opens the source at this quote in a new tab)

Clinical milestones: hallucinations, recurrent falls, dementia, and nursing home placement

“One or more milestones were reached in 53.0%.” (opens the source at this quote in a new tab)
“The risk of contracting a milestone condition during the study was independently predicted by two baseline factors: Higher age (age 70 years or more resulted in a hazard rate (HR) of 3.5 (95% confidence interval 2.3–5.5), p < 0.001) and presence of PD-MCI (HR 2.1 (1.3–3.4), p = 0.003).” (opens the source at this quote in a new tab)
“In these models, we analyzed the baseline factors age, gender, UPDRS motor score, MADRS score and presence or absence of PD-MCI using Enter method.” (opens the source at this quote in a new tab)
“Of the patients who reached the milestones, visual hallucinations appeared after a median of 3.3 (interquartile range 1.3–4.9) years from diagnosis, recurrent falls after 3.8 (2.8–5.2) years, dementia after 4.0 (2.1–4.8) years and nursing home placement after 5.4 (3.9–6.7) years.” (opens the source at this quote in a new tab)
“We recruited 185 patients with incident PD and monitored prospectively every six months through seven years for emergence and consequences of four clinical milestones.” (opens the source at this quote in a new tab)
“The main reason for loss to follow-up was death; only 9 patients (4.9%) withdrew from study follow-up.” (opens the source at this quote in a new tab)
“Median follow-up time was 7.0 (interquartile range (IQR) 6.8–7.1) years.” (opens the source at this quote in a new tab)
“Visual hallucinations represented the earliest and most frequent milestone, and almost 40% had experienced hallucinations during 7 years of follow-up.” (opens the source at this quote in a new tab)
“The two most frequent milestones, visual hallucinations and recurrent falls, were highly reversible (in 69.1% and 64.9%, respectively).” (opens the source at this quote in a new tab)
“Among patients with reversible visual hallucinations, the RRs of experiencing recurrent falls, dementia and nursing home placement were 2.4 (1.4–4.0), 6.6 (3.3–13.2) and 3.5 (1.7–7.3)” (opens the source at this quote in a new tab)
“In patients with reversible recurrent falling status, the RRs of experiencing visual hallucinations, dementia and nursing home placement were 1.8 (1.2–2.8), 4.2 (2.4–7.3) and 4.4 (2.1–9.3), respectively (all p < 0.01), comparable to the overall RRs presented in Table 2.” (opens the source at this quote in a new tab)
“Presence of any milestone was associated with occurrence of other milestones (relative risks 1.9–6.3; all p ≤ 0.001).” (opens the source at this quote in a new tab)
“Overall, 34 PD patients (18.4%) died during the study.” (opens the source at this quote in a new tab)
“The remaining 23 deaths were preceded by one or more milestone conditions in 69.6% of cases.” (opens the source at this quote in a new tab)
“The median (IQR) time from visual hallucinations to death was 2.7 (1.3–4.6) years, whereas recurrent falls preceded death by 2.4 (1.3–2.6) years.” (opens the source at this quote in a new tab)
“Development of one milestone condition resulted in a trend towards increased mortality (RR of death during the study 2.0 (0.9–4.7, p = 0.1)), and suffering two or more milestones resulted in an RR for death of 2.7 (1.1–6.5, p = 0.03).” (opens the source at this quote in a new tab)
“Experiencing two or more milestones increased the risk of death during the study (relative risk 2.7, p = 0.03).” (opens the source at this quote in a new tab)
“No patients admitted to a nursing home ever returned to independent living, and death ensued after 2.1 years on average.” (opens the source at this quote in a new tab)
“For example, the majority (67.6%) of PD patients with visual hallucinations were classified as still having mild disease according to the Hoehn and Yahr scale, whereas only 10.3% were classified as having severe disease.” (opens the source at this quote in a new tab)
“Despite the long follow-up, most patients did not undergo all milestone conditions, and none of the milestones occurred in half or more of patients.” (opens the source at this quote in a new tab)

Milestone present	Relative risk (95% CI) of visual hallucinations	Relative risk (95% CI) of recurrent falls	Relative risk (95% CI) of dementia	Relative risk (95% CI) of nursing home placement
Visual hallucinations	Not applicable	“2.2 (1.4–3.6)”	“6.3 (3.2–12.4)”	“3.3 (1.6–6.6)”
Recurrent falls	“1.9 (1.3–2.7)”	Not applicable	“4.2 (2.5–7.1)”	“4.7 (2.4–9.2)”
Dementia	“3.2 (2.3–4.5)”	“3.7 (2.4–5.8)”	Not applicable	“5.6 (2.9–10.9)”
Nursing home placement	“2.1 (1.5–3.0)”	“3.2 (2.1–5.0)”	“4.0 (2.5–6.4)”	Not applicable

“Each clinical milestone alone more than doubled the risk of death and had a cumulative effect on mortality, with a HR of 10.83 (95% CI 4.39–26.73) in those experiencing all four milestones.” (opens the source at this quote in a new tab)
“Lastly, for those admitted to a nurse-staffed long-term care facility (n = 43), the median time to admittance from baseline was 6.4 years (IQR 4.5–7.6).” (opens the source at this quote in a new tab)

Falls and recurrent falls

“In these studies, 60.5% (range 35 to 90%) of participants reported at least one fall, with 39% (range 18 to 65%) reporting recurrent falls.” (opens the source at this quote in a new tab)
“Around 70% of people with PD who fall do so recurrently and many fall very frequently.” (opens the source at this quote in a new tab)

Hip and non-vertebral fractures

“Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls.” (opens the source at this quote in a new tab)
“The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04).” (opens the source at this quote in a new tab)
“Seventeen studies (14 cohort and 3 case-control), with a total of 2,329,424 participants, were included in the meta-analysis for hip fractures” (opens the source at this quote in a new tab)
“However, there was substantial heterogeneity between results of the studies (I2=87.4%, p value <0.001).” (opens the source at this quote in a new tab)
“The adjusted estimate using the trim and fill method was 2.26, 95% CI: 1.93 to 2.65.” (opens the source at this quote in a new tab)
“Nine cohort studies, with a total of 1,356,711 participants, were included in the meta-analysis for non-vertebral fractures” (opens the source at this quote in a new tab)
“The heterogeneity observed between the studies was not statistically significant (I2=30.1%, p value= 0.18).” (opens the source at this quote in a new tab)
“Overall, the effect size for non-vertebral fractures in male patients with PD (2.26, 95% CI: 1.37 to 3.73), was higher than the one in women (1.82, 95% CI: 1.33 to 2.48), but the confidence intervals overlapped.” (opens the source at this quote in a new tab)
“This is a clinically important increased risk of hip fracture; for example, the risk is similar to the increased risk of hip fracture in analyses of patients who ever used corticosteroids (2.07 in female and 2.62 in male)” (opens the source at this quote in a new tab)
“In a cross-sectional study, BMD was found to be 7% lower than in controls” (opens the source at this quote in a new tab)
“The mortality rate of patients with this disorder has been reported to be doubled after a hip fracture compared with those without the disease” (opens the source at this quote in a new tab)
“A recent study showed that only 40% of the PD patients diagnosed with fragility fractures were receiving evidence-based treatment for osteoporosis” (opens the source at this quote in a new tab)
“The majority of the published studies have data from white/Caucasian population and were mainly oriented in Europe and the USA; therefore, this might have affected the results.” (opens the source at this quote in a new tab)
“The effect of PD medication would also be an interesting subgroup analysis, but it was not included in our priori analyses, so the data were not extracted.” (opens the source at this quote in a new tab)

Subgroup	Hip fracture: studies	Hip fracture: pooled effect size (95% CI)	Non-vertebral fracture: studies	Non-vertebral fracture: pooled effect size (95% CI)
Men	“7”	“2.93 (2.05, 4.18)”	“2”	“2.26 (1.37, 3.73)”
Women	“6”	“1.81 (1.61, 2.04)”	“2”	“1.82 (1.33, 2.48)”
Cohort studies	“14”	“2.34 (1.98, 2.77)”	Not applicable	Not applicable
Case-control studies	“3”	“3.42 (1.72, 6.79)”	Not applicable	Not applicable
Clinical diagnostic criteria reported	“3”	“3.00 (1.86, 4.83)”	“3”	“1.89 (1.37, 2.61)”
Clinical diagnostic criteria not reported	“14”	“2.37 (2.00, 2.79)”	“6”	“1.82 (1.57, 2.10)”
Diagnosis of Parkinson's disease	“14”	“2.36 (1.98, 2.81)”	“8”	“1.80 (1.59, 2.05)”
Diagnosis of parkinsonism	“3”	“2.46 (1.87, 3.26)”	“1”	“1.87 (1.27, 2.76)”
Asia	“3”	“2.39 (2.02, 2.82)”	“1”	“2.05 (1.71, 2.45)”
Europe	“8”	“2.32 (1.87, 2.89)”	“4”	“1.57 (1.45, 1.71)”
Oceania	“1”	“1.45 (1.14, 1.84)”	Not reported	Not reported
United States	“5”	“3.03 (2.26, 4.05)”	“4”	“1.86 (1.58, 2.19)”

Hip fracture sensitivity analysis with a confidence interval that does not contain its point estimate and four references for three removed studies

“A sensitivity analysis was performed using the studies that scored ≥7 out of 9 stars in the Newcastle Ottawa Scale. Three case-control studies were removed from the analysis (28, 36, 37, 40). The overall effect size was found to be 2.34, 95% CI: 1.98, 2.27, which was similar to the one calculated for all the studies (2.40, 95% CI 2.04 to 2.82).” (opens the source at this quote in a new tab)
“In total, three studies had a case-control design (28, 37, 40) and the rest were cohort studies.” (opens the source at this quote in a new tab)

Aspiration pneumonia and causes of death in late-stage disease

“The most common main cause of death was aspiration pneumonia (34%), followed by sepsis (16%), unspecified pneumonia (13%), ileus (5%) and Covid-19 (5%).” (opens the source at this quote in a new tab)

Dysphagia-related complications: aspiration pneumonia, malnutrition, and difficulty swallowing tablets

“Dysphagia is one of the factors contributing to malnutrition or weight loss in PD, together with increased energy expenditure, loss of appetite and sense of smell and intestinal malabsorption” (opens the source at this quote in a new tab)
“A large follow-up study of 252 patients with PD and confirmed aspiration risk revealed that 10% developed pneumonia” (opens the source at this quote in a new tab)
“Cough reflex sensitivity and cough intensity tend to deteriorate in advanced PD, and this predicts silent aspiration” (opens the source at this quote in a new tab)
“This reduced pulmonary clearance explains why pneumonia (although not necessarily aspiration pneumonia) is a main cause of death in PD” (opens the source at this quote in a new tab)
“Since most PD patients are dependent on taking medication multiple times a day, dysphagia for tablets, especially when severe in the off-phase, may have consequences for the effectiveness of medical treatment” (opens the source at this quote in a new tab)