Visiting Professor to the Department of Psychiatry, University of Newcastle upon Tyne
Northumberland Mental Health Trust, St George's Hospital, Morpeth, Northumberland NE61 2NU
Department of Epidemiology and Public Health, University of Newcastle upon Tyne
Correspondence: Professor D.W.K. Kay, 8 Grosvenor Place, Newcastle upon Tyne NE2 2RE. Tel: 0191 281 0249; e-mail: david.kay{at}care4free.net
Declaration of interest Research grants were provided by the Northern Region Locally Organised Research Scheme and by the Medical Research Council.
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ABSTRACT |
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Aims To study survival, place of death and death certification in pre-senile dementia.
Method Patients aged 45-64 were identified from hospital and community sources in the Northern health region (1985-89) and classified as having presenile dementia of Alzheimer type (PDAT) or pre-senile vascular dementia (PVD) by applying an algorithm to case notes. Deaths were ascertained from the National Health Service Central Registry (NHSCR) to 31 December 1998. Survival analysis was performed using the SPSS/PC program, and expected survival calculated from life tables.
Results Median survival time from diagnosis was 6.08 years and did not differ significantly in PDAT and PVD, or by age or gender; 19.3% of deaths occurred at home, 24.5% in nursing or residential homes and 56.3% in hospital; 72.4% of the death certificates mentioned dementia or Alzheimer's disease; 15.4% were still alive.
Conclusions Pre-senile dementia has a variable but usually chronic course, requiring appropriate planning and services.
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INTRODUCTION |
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METHOD |
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The diagnosis of PDAT was further validated by interview, in 1990-92, of 74 (41%) of the 179 algorithm-defined PDAT patients as part of a case-control study of PDAT using the Mini-Mental State Examination (MMSE) (Folstein et al, 1975) and the History and Aetiology Schedule (HAS) (Copeland & Dewey, 1991). Finally, 80% of the main carers of patients in this subgroup were followed up by post in 1995, when all the surviving patients were reported to have considerable impairment in Activities in Daily Living (ADL) (e.g. all required help in dress or bathing and fewer than 10% could feed themselves unaided). In PVD, cases lacking an ICD-9 coding for dementia would have been missed and its incidence rate was not calculated. Deaths were ascertained through the National Health Service Central Registry (NHSCR), which supplied a copy of the death draft entry, giving the certified causes of death. When the entry gave an ICD code, this was entered into our database; when it did not, we supplied the appropriate code. We identified 233 incident cases of pre-senile dementia, of whom six (2.3%) could not be found by the NHSCR and were excluded from the survival analysis, which was based on 227 cases, including the 85 cases of PDAT described by Newens et al (1993) and 142 new cases of pre-senile dementia.
Statistical methods
Non-parametric statistics were used to compare the markedly skewed age
distributions, and the frequencies of nominal variables. The relationship
between diagnoses made from case notes and from algorithms was examined by
McNemar's test. The t-test for independent samples was used to
compare the means of continuous variables with approximately normal
distributions. Survival analysis was performed using the SPSS/PC version 5.0.1
program; subgroups were compared with the Wilcoxon (Gehan) test. The expected
length of survival of persons of age and gender equivalent to those of the
whole cohort was estimated using English life tables for 1990-92
(Office of Population Censuses and
Surveys, 1997). A longevity quotient, equal to the proportion of
expected lifetime survived, was calculated by dividing the observed by the
expected survival and multiplying by 100. The independent contributions of
age, gender, Hachinski score and clinical diagnosis of PDAT or PVD to the
prediction of death or survival and length of survival were further examined
by logistic or multiple regression.
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RESULTS |
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Incidence
The mean annual incidence of PDAT, allowing for missing case notes, was 6.2
per 100 000 of population aged 45-64. The rate for 1989 of 4.3 was
significantly lower than that for 1985-1988 (mean 6.7 per 100 000).
Duration before diagnosis
The median age of onset of symptoms was 59.2 years (range 44-64). The
duration of symptoms of the illness before diagnosis was 3-6 months in 18%,
6-12 months in 37%, 1-2 years in 25%, and over 2 years in 20%. It was
significantly longer (2=13.08, d.f.=4, P=0.011) in
women than in men, and significantly longer (
2=27.02, d.f.=4,
P<0.0001) in PDAT than PVD, for which a duration of over 1 year
was unusual. It was not significantly related to the period survived or to
dead/alive status at the end of observation.
Certificated causes of death
Of the 192 death certificates, 139 specifically mentioned dementia; two
other cases, one with Binswanger's encephalopathy and hypertension, and one
with cerebral atrophy (coroner's post-mortem), in whom the presence of
dementia seemed implicit, were classified with vascular dementia and
unspecified dementia, respectively, making 141 cases with dementia (73.4%).
Table 2 shows that Alzheimer's
disease was specifically mentioned in 61 cases (31.8%) and vascular dementia
in 12 (6.3%), of which 11 were specified as multi-infarct dementia. Dementia
not specified as Alzheimer or vascular was entered in 52 cases (27.1%) (9
senile, 25 pre-senile, 17 unspecified dementia, 1 cerebral atrophy). In 14
cases (7.3%) both Alzheimer's disease or unspecified dementia and
cerebrovascular disease were recorded. In addition, there were 20 (10.4%)
cases of cerebrovascular disease without mention of dementia (CVD). In the
following, CVD refers only to these cases. Included with
dementia or CVD were two cases (0.9%) of Parkinson's disease (one with
dementia and one with cerebral atherosclerosis) and five cases (2.6%) with
epilepsy (two with Alzheimer's disease, one with senile and one with
pre-senile dementia and one with dementia of unspecified type). Dementia was
not recorded on 53 (27.6%) certificates and neither dementia nor CVD on 33
(17.2%) certificates.
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As Table 2 shows, there was
substantial agreement between the cause of death and the diagnosis made by
clinical algorithm. As for the 52 certificated cases of dementia of
unspecified type, 48 (92.3%) were clinically PDAT. Of the 14 cases whose death
certificates recorded both Alzheimer's disease or unspecified dementia and
cerebrovascular disease, 11 were PDAT. Dementia was recorded on the death
certificate significantly less frequently in cases of PVD than of PDAT
(2 with continuity correction=4.71, d.f.=1, P=0.03).
Cerebrovascular disease with or without dementia was recorded in 15.1% of
cases of PDAT and 27.5% of PVD, and CVD alone in 7.9% and 20%, respectively
(Table 2).
Heart disease and other conditions
Heart disease such as myocardial infarction, coronary atherosclerosis,
ischaemic or hypertensive heart disease, or congestive failure, was mentioned
on 36 certificates (18.7%), in 27 (75%) of which it was given as the immediate
cause of death. Heart disease was significantly more common
(2=26.1, d.f.=1, P<0.001) among deaths without
recorded dementia (43.4%) than in those with dementia (9.4%), and among deaths
without recorded cerebral disease of any kind (63.6%) than in those with
cerebral disease (9.4%) (
2=49.5, d.f.=1, P<0.001).
Heart disease was not related to the clinical NINCDS diagnosis of PDAT or PVD.
Respiratory diseases (nearly all bronchopneumonia) were the immediate cause in
73 cases (38%), which was similar in PDAT and PVD. In seven cases, adult onset
diabetes mellitus was the direct or a contributory cause of death; six were
cases of PDAT, but the death certificates showed only two with Alzheimer's
disease, and the others with CVD or heart disease. Renal failure was mentioned
in three PDAT cases.
Gender differences
Alzheimer's disease or unspecified dementia were significantly more
frequent on the death certificates of women, and vascular dementia or CVD on
those of men (2 with continuity correction=4.10, d.f.=1,
P=0.043). Dementia was absent from the death certificates
significantly more often in men than women (
2 with continuity
correction=6.67, d.f.=1, P=0.010).
Survival
Survival refers to survival after diagnosis unless otherwise
stated. Figure 1 shows the
cumulative percentage surviving in PDAT and PVD and the expected survival in
the general population. Table 3
shows the number dying, the cumulative deaths and the number surviving in
successive years in the whole cohort. The difference in median survival
between PDAT (6.09 years) and PVD (6.00 years) was not significant
(P>0.05), and the pattern is so similar
(Fig. 1) that the following
data apply to the whole cohort unless otherwise stated. The median survival
was 6.08 years: 5.97 years in men and 6.22 years in women, an insignificant
difference. For each year of entry, the cohort was reasonably homogeneous in
respect of survival: median survival (years) was 6.0, 6.0, 5.9, 7.0 and 7.0
for the 5 years from 1985 to 1989, and the differences between adjacent years,
and between 1985-87 and 1988-89, were not significant. Of the patients
entering the study in 1985-86, 8.6% were still alive at the end, as were 22.5%
of those entering later. The difference between younger and older patients
(below and above median age at diagnosis) was not significant. Mean age at
death was 65.4 years (s.d. 4.99) (median 66.3, range 49-76), with no
significant differences by gender or diagnosis. Considering only those who had
died, median survival was 5.47 years (mean 5.53, s.d. 2.78). Calculated from
the onset of symptoms, the median survival time of the whole cohort was 7.50
years, and in those who died 6.77 years. Cumulative survival was 64% after 5
years and 20% after 10 years, compared with age/gender-matched survival in the
general population of 93% and 83%, respectively. The proportions of expected
lifetime for which the cases actually survived (the longevity quotient) were
68.5% and 24.2% at the end of 5 and 10 years, respectively.
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Survival of 2 years or less from the onset of disease was associated with
clinical diagnosis of PVD (2 with continuity correction=7.07,
d.f.=1, P=0.008) and death from CVD (
2 with
continuity correction=6.71, d.f.=1, P=0.009). Patients who died with
no mention of cerebral disease on the death certificate had survived for a
significantly shorter time (mean 4.6 years) than those with cerebral disease
(mean 5.7 years) (t=2.13, d.f.=190, P=0.034), and these
groups also differed in mean survival from symptom onset (t=2.77,
d.f.=188, P=0.006). Cases for whom heart disease was given on the
death certificate were also associated with significantly shorter survival
from the onset of symptoms (t=2.39, d.f.=188, P=0.018), but
not from the time of diagnosis (mainly owing to shorter duration of symptoms
before diagnosis). Of the 10 patients (six with PVD) who died within 2 years
of onset, death was due to heart disease or CVD in eight.
When the cohort of non-survivors was divided into two by median length of survival from symptom onset, cerebral disease of any kind was found to have been recorded more frequently in those who survived longer (90.5% v. 76.8%) (P=0.01). Of the 28 patients who had died 10 years or more after the onset of their symptoms, cerebral disease was recorded in 86% (dementia in 64%), and the distribution of causes of death (Table 2) did not differ significantly from that for the remaining 162 cases (P=0.64), though CVD without dementia was a somewhat more common cause of death in the longer-term survivors (21%) than in the remainder (9%).
Prediction
Although neither death nor length of survival were predicted by age, gender
or clinical diagnosis, clinical diagnosis of PVD and higher Hachinski score
were associated with death with CVD or multiinfarct dementia within the study
period. Clinical diagnosis of PDAT and lower Hachinski score were associated
with death with Alzheimer's disease recorded, and female gender was associated
with any mention of dementia. Multivariate analyses gave similar results,
except that the Hachinski score did not add to prediction in the presence of
clinical diagnosis, and age contributed to the prediction of death with
CVD.
Place of death
Among the 192 deaths, 37 (19.3%) died at home, 108 (56.2%) in hospital and
47 (24.5%) in a residential or nursing home. Between the periods 1985-91 and
1992-98 the proportion of deaths at home and in hospital fell and that in
residential and nursing homes increased (2=9.14, d.f.=2,
P=0.01) (Table 4).
More of those patients who had survived longer died in residential or nursing
homes, whereas those whose illnesses had been shorter died at home or in
hospital.
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DISCUSSION |
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With neuropathological diagnosis as the standard, the sensitivity and specificity of a clinical diagnosis of Alzheimer's disease and multi-infarct dementia have exceeded 70% (Mölsä et al, 1985). In the present study a clinical algorithm, modified from NINCDS criteria and based on information in case notes, was used to standardise diagnosis and to reduce the number of categories from three to two (PDAT and PVD); dementia of unspecified type was usually classifiable as PDAT. In other respects, disagreements between case note and algorithmic diagnoses were few.
However, the clinical diagnosis of presenile dementia has been reported to be frequently erroneous (Ron et al, 1979). We had several opportunities to review the illness and discard doubtful or misdiagnosed cases before the survival analysis was undertaken. In the first place, all case note diagnoses had been carefully screened by applying the algorithm, which included memory impairment accompanied by personality change or at least one other cognitive deficit such as dysphasia; interference with social functioning; and illness duration of at least 3 months (Newens et al, 1993). Patients diagnosed by neurologists were younger than those seen by physicians or psychiatrists, but did not differ in other respects. Second, the case notes of readmitted patients were discarded if the final discharge diagnosis was a nondementia disorder. Third, dementia was confirmed clinically for some of the patients with PDAT when an interview with patient and relative was possible. Finally, the carers of these patients later reported a deteriorating course with considerable impairments in activities of daily living, and in no case had the initial clinical diagnosis of dementia been changed (Newens et al, 1995).
On the other hand, there were fewer opportunities to review the diagnosis of PVD, and this group was probably incomplete and possibly unrepresentative, since the clinical algorithm could not be applied to stroke patients with cognitive impairment unless a diagnosis of dementia had also been coded, and it is likely that this was not done in several possible cases.
Incidence
For this reason, no estimate was made of the incidence of PVD. The mean
annual incidence rate of PDAT of 6.2 per 100 000 population aged 45-64 does
not differ significantly from the rate of 7.2 previously reported by Newens
et al (1993), nor
from the rate of 11.1 in Finland
(Mölsä
et al, 1982). The drop in rate was mainly due to a
particularly low rate in 1989, which may have been due to less retrospective
information being available in the final year of the study than in earlier
years. An annual rate of about 7 per 100 000 may be the best estimate from our
data overall.
Death certification
The validity of the clinical diagnosis of presenile dementia is supported
by the death certificates, 70% of which mentioned dementia. While this is
strong evidence that these patients were suffering from dementia, failure to
record dementia does not necessarily mean that dementia was absent. The 24% of
PDAT cases in which there was no mention of dementia is less than the 30%
without mention of dementia in a cohort of patients with a well-established
diagnosis of senile dementia, Alzheimer type
(Burns et al, 1990).
The distinction between PDAT and PVD is also supported
(Table 2). The more frequent
mention of dementia in PDAT than PVD is in agreement with the Scottish study
of Thomas et al
(1997). We did not find
significant differences in other causes of death between PDAT and PVD, whereas
Thomas et al (1997)
found small increases in cardiac disease, vascular disease (other than
cerebrovascular disease) and other disorders as underlying or contributory
causes of death in PVD compared with PDAT. In the present study, the finding
that heart disease as a cause of death was more frequent when neither dementia
nor CVD was present could be due to dementia being considered unimportant when
there was an obvious cause of death, although in the five patients who died
from heart disease within 2 years, confusional states could possibly have been
mistaken for dementia. But it is also possible that cardiovascular factors are
indeed present, not only in PVD but in some cases of PDAT; the Hachinski score
does not distinguish between multi-infarct dementia and mixed dementia (e.g.
Mölsä
et al, 1985).
Cerebrovascular disease
Cerebrovascular disease, with or without dementia, was mentioned on the
certificates in 16% of cases of PDAT. In these cases the direct causes of
death were: vascular dementia (1), cerebral haemorrhage (1), and cerebral
thrombosis (2); and among direct (12) or antecedent (9) causes were
unspecified types of acute stroke or cerebral atherosclerosis. This
association supports a role for vascular factors in Alzheimer's disease
(Stewart, 1998) but requires
confirmation. Neuropathological studies are needed to resolve this question
and to uncover the range of conditions that may present clinically as
pre-senile dementia. Meanwhile, deaths in this cohort will continue to be
flagged by the NHSCR until all the participants in the study have died.
Survival
The median (50%) survival time of 6.08 years from diagnosis in patients
with PDAT, with a maximum follow-up period of 12.5 years, is close to the 6.04
years survived after a maximum follow-up of 7 years in the earlier incidence
cohort (Newens et al,
1993); as already noted there is a 37% overlap between the two
cohorts. Contrary to the findings of some earlier studies (e.g.
Seltzer & Sherwin, 1983),
patients with PDAT usually survived some time before dying. The median
survival of 7.6 years after symptom onset in PDAT is similar to the median
survival of 8.1 years reported in an Israeli population
(Treves et al, 1986). Nor have previous studies of senile dementia of the Alzheimer type (SDAT)
found age of onset to be related to duration of survival or rate of
progression (e.g. Bracco et al,
1994). However, Barclay et al
(1985), studying incident cases
of Alzheimer's disease, found that the longevity quotient 5 years after
diagnosis was considerably lower (46%) in those diagnosed before the age of 65
than in those diagnosed at the age of 65 or later, indicating that, compared
with the normal, younger patients have a decreased life expectancy. In our
study the longevity quotient of 68% after 5 years is more in accord with the
results of Mölsä
et al (1986),
suggesting that survival in Alzheimer's disease is related to a constant
effect of disease progression, relatively independent of age.
Uniformity or diversity?
Our sample was remarkably homogeneous in respect of survival time and
causes of death. Predictive features were few. We found no difference in
median or mean survival between PDAT and PVD. Hier et al
(1989) also failed to find a
significant difference in survival time between patients aged 65 and over with
multi-infarct dementia and those with senile dementia, but
Mölsä et
al (1986) attributed
higher mortality in vascular dementia to the cerebrovascular disease and
stroke. Specific clinical features, such as stroke or hypertension, which
contribute to the Hachinski scale, were not individually identifiable in our
study, but we found an increase in the number of deaths from cerebrovascular
disease and stroke, although not from cardiovascular morbidity, in PVD
compared with PDAT. In a study of deaths in Scottish mental hospitals,
survival after symptom onset was shorter in multi-infarct dementia (5.8 years)
than in PDAT (7.4 years), mainly because of a longer period between onset and
entering hospital in PDAT (McGonigal
et al, 1992). In the present study, also, duration before
diagnosis was longer in PDAT and, as in Scotland, age at onset or gender did
not affect survival in either condition.
Since the absence of post-mortem data must raise questions about diagnosis, survivors and non-survivors were studied further. First, fewer of the patients entering the study in earlier years had survived than of those entering later, suggesting (if the patients in the two time periods are comparable, as they appear to be) that further deaths associated with pre-senile dementia will occur in the more recently recruited patients. Second, there were no significant differences among survivors between those who had survived longer or shorter than the median (n=17 and 18, respectively) in respect of age at diagnosis, gender, type of consultant, head scan, clinical algorithm or duration before diagnosis. Nor were there significant differences in any of these respects between survivors and non-survivors. Third, 31 long-term survivors were compared with 28 patients who had died 10 years or more after onset. The only significant difference was that those who had died were older at the time of diagnosis (mean age 60.8 v. 58.2 years, t=2.75, d.f.=57, P=0.008).
Very short survival (i.e. death within 2 years from symptom onset) was associated with clinical diagnosis of PVD and death from CVD or heart disease. Apart from these cases, cerebral disease was recorded more often in patients who had survived beyond the median; and even in those who had died 10 years or more after onset, cerebral disease of some kind was recorded in 86% (dementia in 64%), and the distribution of causes of death (Table 2) did not differ significantly from that in the remaining cases (P=0.637). The high proportion of deaths in which cerebral disease was mentioned in persons surviving over 10 years from onset suggests that long survival is compatible with a diagnosis of pre-senile dementia. In the cohort with PDAT reported by McGonigal et al (1992), survival ranged from 1.2 to 16 years. Although cases with purely functional psychoses have probably been excluded by our rigorous selection procedures, the failure to specify the type of dementia in 30% of deaths raises the possibility that the sample was heterogeneous as regards the type of brain disease. Yet, except for two cases of Parkinson's disease, no other specific neurodegenerative diseases have been entered on the death certificates (one death from cerebellar degeneration has occurred since the closing date).
Service aspects
Thirty-five (19.3%) patients died at home, but this proportion fell during
the period studied, as did the proportion dying in hospital, whereas the
proportion dying in residential or nursing homes increased. This provides a
minimal estimate of the number of patients cared for at home, since we were
unable to distinguish between patients who were admitted to a general ward
with an acute illness and those who were receiving long-term hospital care.
The changes in the place of death during the period 1985-91 compared to
1992-97 presumably reflect the reduction in the number of NHS beds for the
elderly and the implementation of the National Health Service and Community
Care Act 1990.
Our findings have a number of implications for services. First, they are important for the counselling of relatives, both on an emotional plane and for planning future financial provision and support in individual families (Luscombe et al, 1998). Second, in conjunction with the studies of incidence and prevalence, disabilities and service use, they have an important role in the planning of hospital and community care for populations. Because pre-senile dementia is relatively uncommon, it is difficult for health authorities to commission totally separate services for physically active younger patients (Delany & Rosenvinge, 1995), and a recent survey confirmed that only 12 out of 304 (3.9%) relevant hospital trusts provided a dedicated specialist service for younger people with dementia (Barber, 1997). Some have suggested that the investigation and diagnosis of pre-senile dementia are the domain of neurologists, whereas the caring skills and facilities of psychiatry of old age should be extended to younger patients for long-term management (Allen & Baldwin, 1995). Our study did not include cases of dementia due to specific neurological diseases or alcohol misuse, though these conditions are important components of pre-senile dementia in a wider sense (Ferran et al, 1996). An alternative model, which recognises that the old age psychiatry system may not always be the most appropriate for younger age groups, is to integrate pre-senile dementia within the context of diagnostic and rehabilitative services for all types of neurological and neurodegenerative disease in middle and late-middle age. Our findings suggest that this question merits careful attention.
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CLINICAL IMPLICATIONS AND LIMITATIONS |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication July 14, 1999. Revision received January 18, 2000. Accepted for publication January 19, 2000.