Mortality and Parkinson disease

Methods.

The study population comprised all subjects living in nine municipalities in the southern part of Rogaland, Western Norway, on the prevalence day (January 1, 1993). The population numbered 220,858, with 148,228 inhabitants living in an urban area (the cities Stavanger and Sandnes) and 72,630 in rural areas, seven surrounding municipalities with agriculture as the main occupation. Complete ascertainment of patients with PD was attempted through an extensive search for patients known to the specialist neurologic service, the general practitioners in the area, nursing homes, district nurses, and home health workers.18 Information on all members of the local branch of the PD society was available. The total patient material comprised 245 patients diagnosed with PD in the study area.18 There were 126 women and 119 men. The prevalence rate was 110.9 per 100,000 inhabitants. The diagnosis of PD was based on clinical information, disease development, and response to levodopa as elicited at the baseline interview and from the hospital records. To achieve high diagnostic specificity as well as high sensitivity, a diagnostic classification of clinically definite, probable, or possible PD was used.19 Clinical definite PD required that a patient had resting tremor and at least two more cardinal signs: akinesia, rigidity, or postural abnormalities. Definite PD had unilateral onset and asymmetric development, and the response to a dopaminergic agent was good to excellent. For a diagnosis of probable PD, the patient had to fulfill at least two of the four cardinal signs. Resting tremor was not mandatory, and a maximum of one of the following atypical clinical features could be present: 1) mild dementia or clinically relevant autonomic failure at disease onset, 2) symmetric disease presentation, 3) a moderate response to a dopaminergic agent, or 4) any other atypical finding. For possible PD, the patient had at least two of the four cardinal signs and the response to a dopaminergic agent was at least moderate. Mild-to-moderate dementia and autonomic failure at disease onset was allowed. Patients with other neurologic diagnoses or the presence of radiologic structural brain abnormalities compatible with diagnoses other than PD were excluded. All patients fulfilled conventional diagnostic criteria for PD.20

The study period was 8 years, from January 1, 1993, to December 31, 2000. No patients were lost to follow-up. All patients were interviewed and examined by a neurologist at baseline (1993) and thereafter the surviving patients were invited to attend a new examination and follow-up in 1997 and 2001. The clinical evaluation included the Unified PD Rating Scale (UPDRS),21 including the Hoehn and Yahr staging system. Cognitive impairment was evaluated by the Mini-Mental State Examination (MMSE)22 and depressive symptoms were measured by the Montgomery and Åsberg Depression Rating Scale (MADRS).23 The age at onset of the disease was determined from the history of symptoms reported by patients and relatives.

The date of death was obtained from the National Population Register of Norway. In Norway a death certificate is filled out by a doctor for all deceased persons soon after death. The certificate is then sent to the local police authority in the municipality where the person had been living, and the information is collected in a national registry at Statistics Norway. As controls, we used mortality rates of the Norwegian population that were available in 1-year intervals for all involved birth cohorts and both sexes during the study period. Population data for the county of Rogaland were not significantly different from national data.

The study was approved by the Norwegian regional ethics committee.

Results.

On January 1, 1993 (baseline), 245 patients with idiopathic PD were identified in the southern part of Rogaland, Western Norway, and included in the study (table 1). A total of 126 of the patients were women and 119 were men. The mean age of the total patient group was 73.5 years (SD 8.4). The duration of disease was 9.0 years (SD 5.8), and mean Hoehn and Yahr stage was 2.8 (SD 1.1). Almost all patients (97%) were treated with levodopa. The patients were also classified according to diagnostic accuracy, with 135 patients in the group with clinical definite PD, 74 with probable PD, and 36 with clinical possible PD. Demographic characteristics of each of the diagnostic categories are presented in table 2. The patients diagnosed as clinical probable and possible PD had more cognitive impairment than patients with definite PD. Measured by the Hoehn and Yahr stage they also had a more advanced disease. UPDRS score, however, was not significantly different in the three accuracy categories.

During the 8-year follow-up period 142 patients (63 women and 79 men) died. Descriptive patient data at baseline for the 142 patients who died and for those who survived 8 years from baseline are presented in table 1. The patients who died during the follow-up period were, as expected, older, and had a more advanced disease, measured by the UPDRS and the Hoehn and Yahr staging system, than the patients who were still alive at the conclusion of the study.

The main findings on mortality are presented in table 3. The SMR for the whole cohort was 1.52 (95% CI 1.29 to 1.79) indicating a higher mortality rate for patients with PD than in a Norwegian population with a comparable distribution by age and sex. Based on these results the calculated life expectancy for patients with PD was decreased by 11.5 (95% CI 6.8 to 16.9) months compared to the general population in the 8-year follow-up period. Figure 1A shows the survival curve for the total group. The figure shows that after 8 years 62% of the patients with PD are deceased, whereas only 43% are deceased in the control population.

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Figure 1. Observed patient survival of the total patient group and categorized by sex. A = Total patient group, B = female, C = male. Smooth line is the expected survival; stepped line is the observed survival with 95% CI.

Figure 1, B and C show that both men and women had a higher death rate than expected (women SMR 1.49, men SMR 1.54). There was no significant difference between the sexes.

Among PD patients who were younger than 70 years at baseline (1993) the survival was not significantly different from the survival of the general population (figure 2A). The number of patients with PD in this age group was small, however. In the age group 70 to 80 years the SMR for PD patients was 1.76 (CI 1.40 to 2.22) (figure 2B). For patients 80 years and older the increase in mortality rate was not significantly different from the general population (figure 2C).

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Figure 2. Observed patient survival categorized by age in 1993 (A–C) and at symptom onset (D–F). A = <70 years, B = 70–80 years, C = >80 years (age in 1993), D = <60 years, E = 60–70 years, F = >70 years (age at symptom onset). Smooth line is the expected survival; stepped line is the observed survival with 95% CI.

We also divided the patients into groups by age when first diagnosed with PD. There was no significant difference between the age groups’ SMR (figure 2, D through F).

Patients with dementia (MMSE <24) had a higher mortality rate (SMR 1.61, CI 1.25 to 2.09) than nondemented patients (SMR 1.46, CI 1.17 to 1.83).

In the group of patients with clinical possible PD an unknown proportion is expected to have another cause for their parkinsonism than idiopathic PD. To avoid this confounding factor for the analyses we examined the SMR for the remaining group of patients (definite and probable PD) and found that the SMR decreased to 1.42 and for definite PD only to 1.35. The SMR for patients with clinical possible PD was as high as 1.99 (see figure 3). The proportion of patients with definite PD still alive after 8 years was 55%, compared to 67% in the comparable general population. The calculated life expectancy was reduced by 6.5 months (95% CI 0.9 to 13.7) after 8 years for patients with clinical definite PD.

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Figure 3. Observed patient survival categorized by diagnostic accuracy. A = Definite PD, B = definite and probable PD, C = possible PD. Smooth line is the expected survival; stepped line is the observed survival with 95% CI.

Discussion.

This study shows that in spite of modern treatment, patients with PD have a decreased life expectancy compared to the general Norwegian population with the same composition of sex and year of birth. Our patient cohort comprises all patients with PD in the study area, and defined diagnostic criteria were applied. The mortality rate was increased for both sexes and in all age groups of disease onset. In contrast, we found that patients with a clinical picture that indicated a high probability for idiopathic PD had a lower mortality rate than patients with more atypical clinical findings. This study indicates that survival for patients with idiopathic PD is only modestly reduced.

Few studies of mortality in PD have used community- or population-based cohorts. Mortality studies based on patient groups from specialized centers or pharmacy drug-sale rosters may give a selection bias that will induce either an over- or underestimate of the true survival of patients with PD. The information from death certificates for case identification will also give inaccurate results because of the inconsistent reporting of PD as a cause of death. In this study we have included all PD patients known to the health care system in the study area. Patients not seeking medical care would be missed by this method. Because PD has a characteristic clinical picture and significant associated disability, most cases should have been identified and included in the study.

The calculated relative mortality for patients with PD was in this study based on a control population that were derived from Norwegian Statistics, which has a complete database over all inhabitants in Norway and contains all relevant demographic information on each individual from birth and until death. This database has in this study provided the mortality information on the PD patients and the control population that was derived from the complete Norwegian population. The controls were, however, not examined and the possibility that there were individuals with PD could not be eliminated, nor could other associated risk factors such as dementia be measured.

The applied method of data handling gives a high accuracy and validity of the findings in the study. The statistical approach for analyzing the mortality data in this cohort study has been developed to take into consideration all possible demographic confounders that could distort the results. The prospective study design with clinical examinations every fourth year and the rather long follow-up period of 8 years should further secure a high quality on the data from this study.

Several investigators have shown that 25 to 30% of patients with clinically diagnosed PD have other diagnoses than idiopathic PD at autopsy.20 In this study we have applied a diagnostic classification that diagnoses the patients with a different level of accuracy for a correct diagnosis. All patients fulfill traditional criteria for PD and the 245 patients were selected from a group of 400 patients with possible parkinsonism who were examined for this study at baseline. The patients with clinical definite PD fulfill diagnostic criteria that have been shown to have a 95% specificity at autopsy.30 In this group of patients with a high probability for idiopathic PD the mortality rate was the lowest observed in the study. This shows that in studies of mortality, inclusion of patients with a higher probability for having alternative causes of parkinsonism, like multiple system atrophy, corticobasal ganglionic degeneration, or progressive supranuclear palsy, will give the false impression that PD results in a shorter than the real life expectancy. The allowance of dementia in the less stringent categories may also explain some of the increased risk of death, as both cognitive impairment and extrapyramidal signs have been shown to be predictive of mortality.13 Even though patients with other neurologic diagnoses were clinically excluded from the study, it is possible that some of the patients in the probable or possible PD categories may have had either diffuse Lewy body disease or PD plus Alzheimer disease.

In fact, the SMR for patients with clinical definite PD was only 1.35 and the calculated shorter life expectancy over 8 years would at average be 6.5 months. In a previous study we have shown that twice as many PD patients (20%) die from pneumonia as in the general population (9%).31 This finding together with the results from the present study indicate that with modern treatment the majority of patients with idiopathic PD will have a survival close to normal. A rather small but significant group of PD patients develop a severe end-stage parkinsonism that leaves them bedridden with increased risk of fatal infections.

During the 1970s a very low mortality rate for patients with PD was observed. These findings were followed by an increase in the 1980s. This has been explained by the introduction of levodopa therapy in the 1970s that prevented the deaths of a proportion of elderly patients who lived an additional 5 years on average. When this group died, they gradually added to the “expected” deaths to create an increase or “catch-up” in mortality.5 It was therefore even more important to analyze the situation in recent years when a steady state has developed.