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

Natural history, survival, and mortality

9 evidence topics · 9 sources

Prodromal phase before motor diagnosis

“Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible.” (opens the source at this quote in a new tab)
“we proposed that early PD should be divided into three stages: preclinical PD” (opens the source at this quote in a new tab)
“(neurodegenerative processes have commenced, but there are no evident symptoms or signs); prodromal PD (symptoms and signs are present, but are yet insufficient to define disease); and clinical PD (i.e., diagnosis of PD based on presence of classical motor signs).” (opens the source at this quote in a new tab)
“The speed of progression from prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level.” (opens the source at this quote in a new tab)
“Polysomnogram-proven RBD: Prospective studies show that more than 75% will develop disease” (opens the source at this quote in a new tab)
“Some studies in cohorts (e.g., RBD cohorts) have clearly documented prodromal durations of >20 years in duration.” (opens the source at this quote in a new tab)
“Based upon an overall assessment of the literature, we posited an average prodromal period of 10 years, but this was extremely subjective; the true value may differ considerably.” (opens the source at this quote in a new tab)

Postural instability, dependency, dementia, and death in population-based incidence cohorts

“In 883 population‐based incident patients, median age at motor symptom onset was 69.2 years. Median time to postural instability and functional dependency was 7.4 years. Dementia affected 49.6% by 10 years and 54.7% had died by 12 years (median survival 9.4 years).” (opens the source at this quote in a new tab)
“In incidence cohorts, overall PD prognosis is worse than previously suggested, with key outcomes often occurring early.” (opens the source at this quote in a new tab)

Mortality relative to people without Parkinson's disease

“Eighty-eight studies were included in the review with variable study methods and quality.” (opens the source at this quote in a new tab)
“Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity.” (opens the source at this quote in a new tab)
“Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5.” (opens the source at this quote in a new tab)
“The overall mortality ratio in the inception cohorts (9 studies; 1,801 patients; median follow-up duration, 9 years) was 1.52 (95% CI, 1.25-1.78), but heterogeneity was high” (opens the source at this quote in a new tab)
“Most of the heterogeneity was because of a single study (Hoehn, 1967)” (opens the source at this quote in a new tab)
“and when this study was removed, the overall mortality ratio was 1.41 (95% CI, 1.28-1.55) with low heterogeneity” (opens the source at this quote in a new tab)
“The non-inception cohorts (33 studies; 27,480 patients; median follow-up duration, 7 years) had mortality ratios ranging from 0.90 to 3.79, with major heterogeneity” (opens the source at this quote in a new tab)
“A funnel plot (Supplemental Data Figure 1) did not show any evidence of publication bias or other small-study effect (Egger’s test, P = 0.87).” (opens the source at this quote in a new tab)
“Univariable metaregression of sex on these data showed no significant differences between males and females (P = 0.17).” (opens the source at this quote in a new tab)
“Most mortality ratios lay between 1.2 and 2.4, but, because of the major heterogeneity in the included studies, calculation of an overall measure was inappropriate.” (opens the source at this quote in a new tab)
“Forty-five studies (27,458 patients) reported survival proportion at specific times” (opens the source at this quote in a new tab)
“The regression coefficient was –0.045 (95% CI, –0.056-0.033).” (opens the source at this quote in a new tab)
“On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity.” (opens the source at this quote in a new tab)
“Eighteen studies reported median survival, 5 inception and 13 non-inception cohorts (Supplemental Data Table 6), which ranged from 6 to 22 years.” (opens the source at this quote in a new tab)
“Meta-analysis of 10 studies (1,306 patients) reporting the mean disease duration at death (Fig. 4) showed major heterogeneity” (opens the source at this quote in a new tab)
“In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years.” (opens the source at this quote in a new tab)
“Increasing age and presence of dementia were most commonly associated with increased mortality.” (opens the source at this quote in a new tab)
“Treatment also may alter prognosis over time, but we did not find any robust evidence that L-dopa has reduced mortality, and we are not aware of data to suggest that any other treatments alter survival.” (opens the source at this quote in a new tab)
“Only 5 studies met all 4 quality criteria.” (opens the source at this quote in a new tab)
“Most of the studies in this review were from Europe or North America, so generalizability to other geographical areas may be limited.” (opens the source at this quote in a new tab)

Independent predictors of mortality across cohort studies

“Twenty-one studies reported independent predictors of mortality” (opens the source at this quote in a new tab)
“Several studies did not report negative findings, so quantitative analysis of these data was not possible.” (opens the source at this quote in a new tab)

Prognostic factor	Studies finding the factor independently associated with increased mortality / studies that examined the association
Increasing age, at onset or at recruitment	“15/17”
Presence of dementia	“9/13”
Male sex	“6/17”
Higher Hoehn and Yahr stage	“5/8”
Postural instability and gait difficulty phenotype, prominent bradykinesia, or lack of tremor	“4/8”
Higher parkinsonian impairment score	“3/6”
Presence of psychosis or hallucinations	“2/4”
Presence of extensor plantar response	“2/2”

Mortality and causes of death over 15 and 20 years in a levodopa-era incident cohort

“The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms.” (opens the source at this quote in a new tab)
“Eighty-two deaths were observed but only 44 were expected.” (opens the source at this quote in a new tab)
“The excess of observed deaths was 86% (SMR, 1.86; 95% confidence interval [CI], 1.48–2.31; P < 0.001).” (opens the source at this quote in a new tab)
“The mean age of death was 75.5 years (SD = 8.1): 74.8 years (SD=7.9) for men and 76.4 (SD = 8.3) for women.” (opens the source at this quote in a new tab)
“Overall, the median time from onset of disease to death was 12.2 years (95% CI, 10.3–14.0 years).” (opens the source at this quote in a new tab)
“For men, the median survival was 11.9 years (95% CI, 9.7–14.0 years), and for women 12.9 years (95% CI, 9.6–16.1 years).” (opens the source at this quote in a new tab)
“The difference in survival between men and women and the difference between randomization groups was not statistically significant.” (opens the source at this quote in a new tab)
“Patients randomly assigned to L-dopa survived for a median of 13.1 years (95% CI, 10.5–15.6 years), whereas patients randomly assigned to bromocriptine survived for a median of 11.6 years (95% CI, 8.7–14.4 years).” (opens the source at this quote in a new tab)
“Variables that were statistically significant univariately to predict death by 15 years were older age at onset (P < 0.001), Hoehn and Yahr Stage 3 at baseline (P < 0.003), rapid prestudy disease progression rate (P < 0.005), imbalance at baseline (P < 0.03), dementia at baseline (P < 0.05), increased tremor score at baseline (P < 0.02), dementia noted within 15 years (P < 0.001), and imbalance developing within the 15 years (P < 0.001).” (opens the source at this quote in a new tab)
“In multivariate analysis, the variables were the older the age of onset and the higher the risk of mortality (P < 0.001), increasing by approximately 15% per year of age.” (opens the source at this quote in a new tab)
“Imbalance noted within 15 years increased the risk of death almost threefold (P < 0.03).” (opens the source at this quote in a new tab)
“pneumonia being the most common cause (22 of 82, 27%) with a SMR >10.” (opens the source at this quote in a new tab)
“Parkinson’s disease was considered to have contributed to the deaths of 43 patients (52%) because of pneumonia, inanition, pulmonary embolism, suicide, and patients who were Stage 5 who had cardiovascular or cerebrovascular events but who were considered unsuitable for rehabilitation.” (opens the source at this quote in a new tab)
“Significantly lower than expected death rates were observed from carcinoma (12 vs. 24.2 expected; SMR, 0.50; 95% CI, 0.26–0.87).” (opens the source at this quote in a new tab)
“Deaths due to cardiovascular disease (15 vs. 13.5 expected) were not significantly increased.” (opens the source at this quote in a new tab)
“In this study, the SMR is 1.58 at 10 years and 1.86 at 15 years” (opens the source at this quote in a new tab)

“After 20 years follow-up of newly diagnosed patients with Parkinson’s disease (PD), 100 of 136 (74%) have died.” (opens the source at this quote in a new tab)
“The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1.” (opens the source at this quote in a new tab)
“In the first 3 years, five died compared with an expected 9.2 deaths (SMR = 0.5, 95% CI 0.2–1.1).” (opens the source at this quote in a new tab)
“Between 3 and 20 years, 95 died compared with an expected 38.7 deaths (SMR = 2.5, 95% CI = 2.0–3.0).” (opens the source at this quote in a new tab)
“The SMR was similar for the periods 3 to 5, 5 to 10, 10 to 15, and 15 to 20 years (chi-square test statistic for between period differences = 2.6 for 3 degrees of freedom, P = 0.5) but showed a trend to increase with duration of disease compared to the age matched Australian population after falling in the early years of treatment: SMR = 0.5 at 0 to 3 years, 1.8 at 3 to 5 years, 2.3 at 5 to 10 years, 2.7 at 10 to 15 years and 3.1 at 15 to 20 years.” (opens the source at this quote in a new tab)
“The mean age at death was 76 years (SD = 7.5), 75 years for men and 78 years for women after a mean of 121 and 132 months from entry to the study, respectively.” (opens the source at this quote in a new tab)
“The median time from historical onset of disease to death was 12.4 years.” (opens the source at this quote in a new tab)
“Pneumonia was the most common cause of death, 26 of 103 (25%), generally occurring in Hoehn and Yahr stage 5.” (opens the source at this quote in a new tab)
“PD was considered to have been a significant contributor to the death of 55 of 103 (54%).” (opens the source at this quote in a new tab)
“Once dementia was diagnosed (excluding those diagnosed at baseline), the median survival was 54 months.” (opens the source at this quote in a new tab)
“Although dementia was predictive of death (P = 0.001) univariately, it is so strongly associated with increasing age as to render it insignificant when age is corrected for multivariately.” (opens the source at this quote in a new tab)

Six-year survival among United States Medicare beneficiaries with incident Parkinson's disease

“Retrospective cohort study of 138,000 Medicare beneficiaries with incident PD were identified in 2002 and followed through 2008.” (opens the source at this quote in a new tab)
“Thirty-five percent of PD cases lived more than six years.” (opens the source at this quote in a new tab)
“Sex and race significantly predicted survival: female (HR 0.74, 0.73– 0.75), Hispanic (HR 0.72, 0.65–0.80) and Asian (HR 0.86, 0.82–0.91) cases had a lower adjusted risk of death than white males.” (opens the source at this quote in a new tab)
“Dementia/cognitive impairment, diagnosed in 69.6% of cases, most often in Blacks (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR 1.72, 1.69–1.75).” (opens the source at this quote in a new tab)

Trends in Parkinson's disease mortality in the United States, 1999 to 2019

“Analyses focused on the data from 479,059 deaths due to PD from 1999 to 2019.” (opens the source at this quote in a new tab)
“The age-adjusted mortality from PD increased from 5.4 (95% confidence interval [CI] 5.3–5.5) per 100,000 population in 1999 to 8.8 (95% CI, 8.7–8.9) per 100,000 population in 2019, with an average annual percent change of 2.4%” (opens the source at this quote in a new tab)
“Age-adjusted PD mortality rates were twice as high in men as in women and were greater in White individuals than those from other racial/ethnic groups.” (opens the source at this quote in a new tab)
“Between 1999 and 2019, the number of deaths from PD in the US population was more than doubled, from 14,593 to 35,311” (opens the source at this quote in a new tab)
“The state-level estimates of the increases ranged from 3.1 to 8.4 per 100,000 in 1999 to 4.6 to 11.7 per 100,000 in 2019” (opens the source at this quote in a new tab)
“Death resulting from PD was ascertained by its designation as the underlying cause of death in death certificates with codes G20 to G21 of the ICD-10, which was implemented in 1999.” (opens the source at this quote in a new tab)
“Thus, in our study, only PD as the underlying cause of death was counted.” (opens the source at this quote in a new tab)

Group	Deaths, 1999	Death rate per 100,000 (95% CI), 1999	Deaths, 2019	Death rate per 100,000 (95% CI), 2019	Average annual percent change (95% CI), 1999 to 2019
All ages, crude rate	“14,593”	“5.2 (5.1–5.3)”	“35,311”	“10.8 (10.6–10.9)”	“3.6 (3.0–4.2)”
All ages, age-adjusted rate	Not applicable	“5.4 (5.3–5.5)”	Not applicable	“8.8 (8.7–8.9)”	“2.4 (1.8–3.0)”
Aged 64 years or younger, crude rate	“295”	“0.1 (0.1–0.1)”	“876”	“0.3 (0.3–0.3)”	“5.0 (3.4–6.6)”
Aged 65 to 74 years, crude rate	“2,020”	“11.0 (10.5–11.4)”	“5,276”	“16.8 (16.3–17.2)”	“1.9 (1.4–2.5)”
Aged 75 to 84 years, crude rate	“7,110”	“58.2 (56.8–59.5)”	“14,902”	“93.3 (91.8–94.8)”	“2.2 (1.8–2.5)”
Aged 85 years or older, crude rate	“5,168”	“124.4 (121.0–127.8)”	“14,257”	“215.9 (212.3–219.4)”	“2.7 (2.0–3.5)”
Men, age-adjusted rate	“8,262”	“8.4 (8.2–8.6)”	“21,592”	“13.1 (13.0–13.3)”	“2.2 (1.7–2.7)”
Women, age-adjusted rate	“6,331”	“3.7 (3.6–3.8)”	“13,719”	“5.8 (5.7–5.9)”	“2.1 (1.7–2.5)”
Hispanic, age-adjusted rate	“389”	“3.5 (3.2–3.9)”	“2,126”	“6.5 (6.2–6.8)”	“3.0 (2.7–3.3)”
Non-Hispanic White, age-adjusted rate	“13,475”	“5.8 (5.7–5.9)”	“30,307”	“9.7 (9.6–9.8)”	“2.5 (1.9–3.1)”
Non-Hispanic Black, age-adjusted rate	“502”	“2.4 (2.2–2.6)”	“1,655”	“4.7 (4.5–5.0)”	“3.5 (2.7–4.3)”
Non-Hispanic, other, age-adjusted rate	“200”	“3.4 (2.9–3.8)”	“1,182”	“5.6 (5.3–6.0)”	“2.5 (1.7–3.4)”
Large central metropolitan, age-adjusted rate	“3,894”	“5.1 (5.0–5.3)”	“8,907”	“8.2 (8.1–8.4)”	“2.4 (1.7–3.1)”
Large fringe metropolitan, age-adjusted rate	“3,400”	“5.7 (5.5–5.9)”	“9,008”	“9.2 (9.0–9.4)”	“2.4 (1.7–3.2)”
Medium metropolitan, age-adjusted rate	“3,136”	“5.6 (5.4–5.8)”	“7,768”	“9.0 (8.8–9.2)”	“2.4 (1.5–3.2)”
Small metropolitan, age-adjusted rate	“1,592”	“6.0 (5.7–6.2)”	“3,707”	“9.3 (9.0–9.6)”	“2.3 (2.0–2.7)”
Micropolitan, age-adjusted rate	“1,510”	“5.3 (5.0–5.5)”	“3,464”	“9.1 (8.8–9.5)”	“2.5 (2.1–2.9)”
Noncore, age-adjusted rate	“1,061”	“4.4 (4.2–4.7)”	“2,457”	“8.3 (8.0–8.7)”	“2.9 (2.4–3.4)”

Global deaths and disability-adjusted life-years

“Parkinson's disease caused 3·2 million (95% UI 2·6–4·0) DALYs and 211 296 deaths (95% UI 167 771–265 160) in 2016.” (opens the source at this quote in a new tab)
“From 1990 to 2016, age-standardised prevalence, DALY rates, and death rates increased for all global burden of disease regions except for southern Latin America, eastern Europe, and Oceania.” (opens the source at this quote in a new tab)

Motor complications and survival in a population-based cohort

“At 13 years, 61 of 141 patients were alive.” (opens the source at this quote in a new tab)
“Both early motor fluctuations and levodopa‐induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years).” (opens the source at this quote in a new tab)