ARTICLES
Articles
Efficacy of rivastigmine in dementia with Lewy bodies: a
randomised, double-blind, placebo-controlled international study
Ian McKeith, Teodoro Del Ser, PierFranco Spano, Murat Emre, Keith Wesnes, Ravi Anand, Ana Cicin-Sain,
Roberto Ferrara, René Spiegel
Summary
Background Dementia with Lewy bodies is a common form of
dementia in the elderly, characterised clinically by fluctuating
cognitive impairment, attention deficits, visual hallucinations,
parkinsonism, and other neuropsychiatric features. Neuroleptic
medication can provoke severe sensitivity reactions in patients
with dementia of this type. Many deficits in cholinergic
neurotransmission are seen in the brain of patients with Lewy-
body dementia; therefore, drugs enhancing central cholinergic
function represent a rationally-based therapeutic approach to
this disorder. Rivastigmine, a cholinesterase inhibitor, was
tested in a group of clinically characterised patients with Lewy-
body dementia.
Methods A placebo-controlled, double-blind, multicentre study
was done in 120 patients with Lewy-body dementia from the
UK, Spain, and Italy. Individuals were given up to
12 mg rivastigmine daily or placebo for 20 weeks, followed by
3 weeks rest. Assessment by means of the neuropsychiatric
inventory was made at baseline, and again at weeks 12, 20,
and 23. A computerised cognitive assessment system and
neuropsychological tests were also used, and patients
underwent close medical and laboratory safety analysis.
Findings Patients taking rivastigmine were significantly less
apathetic and anxious, and had fewer delusions and
hallucinations while on treatment than controls. Almost twice
as many patients on rivastigmine (37, 63%), than on placebo
(18, 30%), showed at least a 30% improvement from baseline.
In the computerised cognitive assessment system and the
neuropsychological tests, patients were significantly faster and
better than those on placebo, particularly on tasks with a
substantial attentional component. Both predefined primary
efficacy measures differed significantly between rivastigmine
and placebo. After drug discontinuation differences between
rivastigmine and placebo tended to disappear. Known adverse
events of cholinesterase inhibitors (nausea, vomiting,
anorexia) were seen more frequently with rivastigmine than
with placebo, but safety and tolerability of the drug in these
mostly multimorbid patients were judged acceptable.
Institute for the Health of the Elderly, University of Newcastle upon
Tyne, Newcastle upon Tyne, UK (Prof I McKeith FRC); Section of
Neurology, Hospital Severo Ochoa, Leganes, Spain (T Del Ser MD);
Facoltà di Medicina e Chirurgia, Università degli studi Brescia,
Brescia, Italy (Prof P Spano MD); Department of Neurology,
Instanbul Medical School, Turkey (Prof M Emre MD); Cognitive Drug
Research Ltd, Reading, UK (K Wesnes PhD); Novartis
Pharmaceuticals Corporation, New Jersey, USA (R Anand MD);
Novartis Pharma AG, Basel, Switzerland (A Cicin-Sain MD;
Prof R Spiegel PhD); and Novartis Farma, Milan, Italy (R Ferrara PhD)
Correspondence to: Prof I McKeith Institute for the Health of the
Elderly, University of Newcastle upon Tyne, Newcastle upon Tyne
NE4 6BE, UK
(e-mail: i.g.mckeith@ncl.ac.uk)
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Interpretation Rivastigmine 6–12 mg daily produces
statistically and clinically significant behavioural effects in
patients with Lewy-body dementia, and seems safe and well
tolerated if titrated individually.
Lancet 2000; 356: 2031–36
See Commentary page 2024
Introduction
Dementia with Lewy bodies has been recognised during
the past decade as a common form of dementia in the
elderly, accounting for 15–25% of dementia
presentations.1,2 Fluctuating cognitive impairment and
attention deficits are usually accompanied by recurrent
visual hallucinations and parkinsonism.3 Delusions,
depressed mood, sleep disturbance, and auditory
hallucinations are common neuropsychiatric features of
Lewy-body dementia. This large patient group poses a
considerable therapeutic challenge since neuroleptic
medication, the mainstay of management of psychosis
and behavioural problems in most other disorders, can
provoke severe, irreversible, and often fatal sensitivity
reactions in this type of dementia.4 A two-fold to three-
fold increased mortality associated with neuroleptic
sensitivity reactions in dementia with Lewy bodies has
been shown by necropsy studies to be at least in part
mediated via acute blockade of postsynaptic dopamine D2
receptors in the striatum.5 Clinicopathological correlative
studies in Lewy-body dementia have also shown extensive
deficits in cholinergic neurotransmission.6 Neocortical
cholinergic activity (assessed by choline acetyltransferase)
is more severely depleted in dementia with Lewy bodies
than in Alzheimer’s disease, a deficit correlated with the
presence of visual hallucinations and global severity of
cognitive impairment. Postsynaptic muscarinic receptors
are better preserved and more functionally intact in
Lewy-body-type dementia than in Alzheimer’s disease,
partly because of the absence of neocortical
neurofibrillary tangle deposition. Therefore, drugs
enhancing central cholinergic function offer a rationally
based therapeutic approach for Lewy-body dementia,7
cognitive and hallucinatory symptoms being the
anticipated targets.8 Preliminary findings from open
studies with cholinesterase inhibitors lend support to this
possibility,9–11 as do reports of patients diagnosed
clinically with Alzheimer’s disease, but responding well to
cholinesterase inhibitor treatments, only to be diagnosed
with Lewy-body dementia at necropsy.12,13
Our objective was to examine the efficacy, tolerability,
and safety of rivastigmine, given twice daily, at doses up
to 12 mg per day, over 20 weeks, in patients with
probable Lewy-body dementia. Rivastigmine is a
cholinesterase inhibitor of the carbamate type and is
symptomatically effective and safe in patients with mild
to moderately-severe Alzheimer’s disease at a dose of
6–12 mg daily.14,15
2031
ARTICLES
Methods
Study population
We enrolled male and female patients who: had a clinical
diagnosis of probable Lewy-body dementia;3 had mild to
moderately-severe dementia as defined by a mini-mental
state examination (MMSE)16 score over nine (no upper
limit); gave written informed consent; had contact on at
least 5 out of 7 days per week with a responsible caregiver;
and were proficient in the language in which psychometric
tests were provided. Exclusion criteria included: severe
extrapyramidal symptoms—ie, a Hoehn and Yahr17 score
over three, or scores over three for rigidity, tremor, or
bradykinesia on the unified Parkinson’s disease rating scale
(UPDRS);18 and asthma or known hypersensitivity to drugs
closely similar to rivastigmine in structure or
pharmacological action. Patients on neuroleptics,
anticholinergics, selegiline, or similar drugs were not
included. Patients were recruited from dementia
assessment clinics in Spain, UK, and Italy by experts in
neurology, psychiatry, and geriatric medicine, experienced
in clinical diagnosis of dementia with Lewy bodies, and
familiar with the use of rivastigmine in Alzheimer’s-disease
populations. Procedures were in accordance with ethical
standards of the responsible committee on human
experimentation and with the Helsinki Declaration as
revised in 1983.
Study design
Treatment duration in our randomised, double-blind,
placebo-controlled, exploratory study was 23 weeks,
including 20 weeks on either rivastigmine or placebo,
followed by a 3-week rest period. Treatment started with
1·5 mg of rivastigmine or placebo given twice a day. Doses
were escalated by 1·5 mg twice daily for a maximum of 2
weeks at each dose until 6 mg twice daily or a maximum
well tolerated maintenance dose was reached. Titration
lasted up to 8 weeks.
A randomisation list was computer generated with a
proprietary computer application, according to a
randomised block design. The various placebo and
treatment blocks were then issued with a medication
number and assigned to consecutive patients in a sequential
order. Two copies of the randomisation list were prepared:
one was used by the packaging department, the other was
kept in a locked location until after the study was
completed. Each investigator, and respective hospital
pharmacist, was given a sealed envelope containing the
individual treatment regimen of patients under their charge.
These envelopes were to be opened only in case of
emergency and were collected after unblinding and verified
for code breaks. All personnel directly involved in the
conduct of the study remained unaware of the treatment
groups until all patients had completed the trial and all data
had been retrieved and finalised for analysis at the time of
database lock.
Rivastigmine and placebo were presented in identical
yellow capsules, size two, and supplied in duplex blister
packs containing 20 capsules for morning and evening
administration over 10 days. These blister packs were
supplied in labelled boxes—ie, one box for each patient and
each dose. Safety evaluations included recording of: adverse
events; electrocardiogram results (at screening, baseline,
and at weeks 4, 12, 20, and 23); cardiovascular vital signs
(every week up to week 8, then at weeks 12, 20, and 23);
and laboratory test outcomes. Adverse events were coded
with a standard glossary, and a central laboratory did all
clinical laboratory examinations. Changes in motor
function and symptoms of parkinsonism were assessed with
the motor examination section of the UPDRS.
2032
For personal use only. Not to be reproduced without permission of The Lancet.
Assessment of efficacy indices were made at baseline, at
weeks 12 and 20, and 3 weeks after drug discontinuation.
Primary efficacy measures were the neuropsychiatric
inventory (NPI)19 and a combined score indicating the
speed of response to selected tests from the cognitive drug
research computerised cognitive assessment system.20 The
NPI assesses 12 behavioural domains based on an interview
with the caregiver. In a previous analysis of NPI baseline
scores in this sample of patients,21 a four item subscore
calculated as the sum of scores for delusions,
hallucinations, apathy, and depression was identified as the
main Lewy-body dementia cluster. Therefore, we used this
subscore (NPI-4) as a primary efficacy criterion. The
computerised cognitive assessment system consisted of tests
of attention, working memory, and episodic memory,
which have previously been shown to be sensitive to effects
of cholinesterase inhibitors in Alzheimer’s disease.22 Since
behavioural slowing and severely impaired attentional
function are key features of Lewy-body dementia, we used
the sum of latencies measured from the computerised
cognitive assessment tests (speed score) as the second
primary efficacy measure, calculated as the unweighted
sum of simple, choice, digit vigilance, numeric working
memory, spatial memory, word recognition, and picture
recognition reaction times.
Secondary efficacy criteria were the clinical global
change-plus (CGC-plus), the total score of NPI items one
to ten (NPI-10), the MMSE, and other combined scores
from the computerised cognitive assessment tests, the
individual tasks, plus additional neuropsychological tests
for executive function and planning (digit symbol
substitution task, trail-making tests A and B, controlled
word association test, Stroop test, and block-design test).
Exploratory outcome variables were the NPI domain scores
for each of the 12 domains and individual subscores of the
computerised cognitive assessment test.
Statistical analysis
No a-priori hypotheses of between-group differences were
made in the planning phase. The sample size was originally
defined as 172 patients on the basis of feasibility
considerations. Because of administrative delays and
recruitment difficulties in some centres, however, the
sample size was reduced to 120. Patients who had at least
one dose of study medication, and had at least one safety
evaluation, were considered for safety analysis. Patients
were classed for efficacy analyses as: classic intent to treat,
traditional last observation carried forward (randomised
patients with at least one assessment while being treated),
and observed cases (randomised patients with review done
while taking rivastigmine at designated assessment times).
A subset of the observed cases dataset, consisting of all
patients who attended the week 23 visit, was considered for
review in the follow-up data set.
The changes from baseline of the NPI-4, NPI-10, and
MMSE were assessed by means of analysis of covariance
(ANCOVA), with baseline values as covariates and
treatment groups and countries as factors. If assumptions
for analysis of covariance were not met, ANOVA was done.
For computerised cognitive assessment scores, changes
from baseline were analysed by means of repeated analysis
of variance measures. As suggested by Cummings,23 the
NPI-4 and NPI-10 scores were also analysed as number of
patients improved by at least 30% from baseline: the
probability of reaching this clinically relevant criterion by
week 20, for both NPI-4 and NPI-10 scores, was
investigated by means of logistic regression, with country,
age, sex, and NPI, UPDRS, and MMSE baseline total
scores as covariates. The week-20 results of the CGC-plus
THE LANCET • Vol 356 • December 16, 2000

scores were analysed by means of Cochran-Mantel-
Haenszel test stratified by country. All tests were two-tailed
and done at the 0·05 level of significance.
Analysis of the following variables was limited to
descriptive statistics and frequency distributions: adverse
events and serious adverse events; abnormalities in
laboratory indices, vital signs, and electrocardiograms; NPI
domain scores for each of the 12 domains; UPDRS single
motor items, plus a subscale of five items (tremor at rest,
action tremor, rigidity, facial expression, and bradykinesia)
that proved independent of severity of cognitive
impairment,24 and which were judged particularly
appropriate for this population.
Results
120 patients were randomised to receive either
rivastigmine or placebo. Their baseline demographic and
background characteristics are described in detail
elsewhere21 and summarised in table 1. The two treatment
groups (59 patients rivastigmine, 61 placebo) were closely
similar in age, sex, and MMSE scores (table 1). Most
patients in both treatment groups (90, 75%) had one, or
more, coexistent medical condition. The most common
medical disorders were musculoskeletal (34, 28%),
cardiovascular (34, 28%), gastrointestinal (25, 21%), and
psychiatric (22, 18%). 108 (90%) patients had fluctuating
cognition with pronounced variations in attention and
alertness; 48 (81%) patients in the rivastigmine, and 45
(74%) of those in the placebo group had recurrent visual
hallucinations, and more than 108 (90%) patients in both
groups had spontaneous motor features of parkinsonism.
53 (89%) patients on rivastigmine and 49 (80%) on
placebo were receiving one or more concomitant drugs at
baseline including: nervous system drugs, mainly
dopaminergic agents (17 [31%] on rivastigmine and 18
[30%] on placebo); hypnotics/sedatives (15 [25%] and 9
[15%]; and antidepressants (11 [19%] and 14 [23%]).
Drugs most frequently discontinued after baseline were
those acting on the nervous system (discontinued in 24
patients) and on the cardiovascular system (11); no major
differences between groups emerged in this respect.
92 patients completed the 20 weeks’ treatment (figure
1) and were available for the observed-cases analysis. A
total of 28 patients (18 rivastigmine, ten placebo)
discontinued the study prematurely. Reasons for
discontinuation were similar in both groups, apart from
withdrawal of consent, which arose more often in the
rivastigmine group than in those on placebo. There were
117 patients available for the last observation carried
forward data set efficacy analysis, and a total of 89
Treatment group
Rivastigmine (n=59) Placebo (n=61)
Age (years)
Mean 73·9 73·9
SD 6·5 6·4
range 57–87 62–85
⭐65* 6 (10·2%) 8 (13·1%)
66–75* 26 (44·1%) 26 (42·6%)
76–85* 26 (44·1%) 27 (44·3%)
>85* 1 (1·7%) 0
Sex
Male* 31 (52·5%) 37 (60·7%)
Female* 28 (47·5%) 24 (39·3%)
MMSE
Mean 17·9 17·8
SD 4·7 4·4
Range 10–29 11–26
*n (%) shown.
Table 1: Baseline characteristics of patients
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
ARTICLES
120 randomised
59 assigned to 61 assigned to
rivastigmine placebo
7 adverse events 7 adverse events
5 withdrawals of 1 died
consent 1 withdrawal of
2 protocol consent
violations 1 protocol
1 treatment violation
failure
2 lost to follow-up
1 other reason
(abnormal
electro-
cardiograph)
41 completed 51 completed
treatment treatment
Figure 1: Trial profile
patients for the medication-free follow-up analysis.
The extent to which patients were able to complete the
computerised and other psychometric tests was variable,
and the amount of data available for analysis varied from
one task to another. The main analysis of computerised
cognitive assessment system speed score consisted of 48
controls and 39 patients taking medication. Similar
numbers were available for many of the subsequent
observed-cases analysis, but many tasks were only done by
some patients; the traditional psychometric measures were
particularly hard for patients, often being completed by less
than half, and in the case of the trail-making version B, less
than a quarter.
By week 8—ie, at the end of the titration period—there
were 48 patients taking rivastigmine. Their mean daily dose
had increased to a maximum of 9·4 mg and showed a
slight decline thereafter. The maximum daily dose
(12 mg) was reached by 27 (56%) of the 48 patients, with
44 (92%) reaching 6–12 mg.
Tolerability and safety
Two deaths were reported in the placebo group (one after
discontinuation) and both were judged as being related to a
coexistent medical condition. More patients on
rivastigmine (54, 92%) than placebo (46, 75%) had adverse
events. As reported previously,14,15 the predominant adverse
events were cholinergic in nature: the frequency of nausea
(22, 37%), vomiting (15, 25%), anorexia (11, 19%), and
somnolence (five, 9%) was significantly higher in the
rivastigmine group than in those on placebo (Fisher’s exact
test). Most adverse events were mild or moderate in both
groups; the occurrence of adverse events rated as severe was
similar for rivastigmine (ten patients) and placebo (eight).
The distribution of severe adverse events by body system
did not differ between the groups, with the exception of
three cases of agitation, rated as severe, on rivastigmine.
Analysis of the UPDRS motor subscale revealed no change
in parkinsonian symptoms on rivastigmine compared with
baseline and placebo. In addition, the UPDRS 5-item score
did not show any change. No significant or clinically
relevant changes with respect to haematological and
biochemical test, urinalysis, and cardiovascular vital signs
(including electrocardiogram) were seen between the
groups. However, there was a time-related trend in the
rivastigmine group for a reduction in body weight (mean
change by week 20: ⫺1·8 kg [SD 3·7] from baseline).
2033
 ARTICLES

Number of Baseline Mean change Comparison

p=0·030 p=0·005 p=0·001
patients mean (SD) from baseline
at week 20
Between-group p 70 63·4
difference
mean (SD)
60 57·4

Percentage of patients
(95% CI)

improving by 肁30%
NPI-4 47·5 Rivastigmine
50
ITT Placebo
Rivastigmine 59 12·2 (8·2) 2·5 (8·4) 40
1·7 (⫺1·1 to 4·6) 0·088
Placebo 61 11·7 (8·6) 0·8 (7·3) 30·2 30·0
27·9
LOCF
30
Rivastigmine 47 12·1 (7·9) 3·1 (9·1) 20
2·3 (⫺0·9 to 5·7) 0·045
Placebo 53 11·2 (8·4) 0·8 (7·4)
OC 10
Rivastigmine 41 12·0 (7·9) 4·1 (8·3)
Placebo 51 11·3 (8·6) 0·7 (7·4)
3·4 (0·06 to 6·6) 0·010 0
ITT LOCF OC
NPI-10
Figure 3: Percentage of patients showing 肁30% improvement
LOCF
Rivastigmine 47 23·2 (15·0) 5·0 (16·2) from baseline on NPI-4 by week 20
3·8 (⫺1·6 to 9·2) 0·048 ITT=intent to treat dataset; LOCF=last observation carried forward
Placebo 53 20·2 (14·2) 1·2 (10·7)
dataset; OC=observed cases dataset.
OC
Rivastigmine 41 22·7 (15·0) 7·3 (13·7)
6·4 (1·4 to 11·5) 0·005
Placebo 51 20·1 (14·4) 0·9 (10·4) baseline at week 20 was significant for all three data sets
NPI-4=four item neuropsychiatric inventory sub-score; ITT=intent to treat dataset; (p=0·017, 0·007, and 0·001 for intent to treat, last
LOCF=last observation carried forward dataset; OC=observed cases dataset; observation carried forward, and observed cases,
NPI-10=ten item neuropsychiatric inventory sub-score.
respectively). This pattern is very similar to that of the NPI-
Table 2: Mean changes from baseline for NPI-4 and NPI-10
4. Symptom domains improving on rivastigmine included
apathy, indifference, anxiety, delusions, hallucinations, and
Efficacy aberrant motor behaviour. A second group of symptom
The mean change from baseline on NPI-4 at week 20 domains (depression/dysphoria, agitation/aggression,
favoured rivastigmine for all three data sets (table 2). The irritability/liability, sleep disorder, appetite, and eating
difference between rivastigmine and placebo for analyses of disorder) did not worsen on treatment (figure 4). For two
the last observation carried forward and the observed cases symptom domains (elation/euphoria, and disinhibition) the
was significant at week 20. For the computerised cognitive number of patients affected at baseline was insufficient to
assessment system speed score, difference between allow any meaningful comparison.
rivastigmine and placebo was significant in all three data A consistent, although non-significant, advantage
sets at week 12 (intent to treat p=0·010; last observation (p=0·085) for rivastigmine was seen in patient showing
carried forward p=0·005; observed cases p=0·002) and at CGC-plus improvement at week 20 (good, moderate, and
week 20 (intent to treat p=0·048; last observation carried minimum) in the observed dataset cases. No significant
forward p=0·046; observed cases p=0·017) (figure 2). The difference between rivastigmine and placebo was seen in
proportion of patients who improved significantly at week mean CGC-plus score. Changes in MMSE scores at week
20—ie, showed at least a 30% reduction from baseline on 20 favoured rivastigmine for all three data sets, although the
their NPI-4 scores—was significantly greater in the differences between treatment groups were not significant.
rivastigmine group for all three data sets (figure 3). The observed cases analysis showed a mean improvement
For the NPI-10 score, difference between treatments, of 1·5 points for patients on rivastigmine, whereas patients
with respect to mean change from baseline at week 20, was on placebo declined by 0·1 points (p=0·072). All other
significant for both the last observation carried forward and
observed cases data sets (table 2). The percentage of
–3·00
patients showing improvement by at least 30% from Rivastigmine
Mean change from baseline (week 20)

–2·50 Placebo
Improvement

–2·00
–5000
–1·50
–4000 Rivastigmine
Improvement

Placebo –1·00
–3000
–0·50
–2000
0
Deterioration

–1000
ms

0 0·50
Deterioration

1000 1·00
2000 1·50
3000 2·00
ns

es agg ions

ria

hy eup y
ia

er Irrit inhi e
m lity/ on

eh ty
ur

so p
s

4000
sp n

er
c

ee
o

Ap ion nxie

r b bili
r

io
Di eren
sio

ti
ho

ho
n/ ssi

rd
Sl
bi

av
at

la
lu

A
sio re

5000
in

ff
De

dy

di
c

di
/
ita allu

s
/in

g
i

Baseline Week 12 Week 20 Week 23

ab

tin
/

ot
De ion
H

at

ea
El

at
t

d
nt

Treatment phase Follow-up

pr

an
Ag

ra

e
tit
Ab

Figure 2: Computerised cognitive assessment system speed

pe
Ap

score: mean change (95% CIs) from baseline

Mean values (rivastigmine 1084 and 1318 ms; placebo ⫺2503 and
⫺991 ms) and 95% CIs in observed cases dataset at weeks 12 and 20 Figure 4: Mean changes (95% CIs) of individual NPI items—
were close to those shown for follow-up. observed-cases analysis

2034 THE LANCET • Vol 356 • December 16, 2000

For personal use only. Not to be reproduced without permission of The Lancet.

derived measures from the computerised cognitive
assessment systems tasks showed a pattern in favour of
rivastigmine, particularly measures combining speed scores
from the three attentional tests. Furthermore, the
individual computerised cognitive assessment system tasks
and neuropsychological tests all significantly favoured
rivastigmine. These data will be described more fully
elsewhere.
At 3-week medication-free follow-up, the mean
differences from baseline for both primary efficacy variables
were smaller than at week 20, and the differences between
both groups were no longer significant, although results still
favoured the rivastigmine group (for NPI-4 follow-up, see
figure 5). Figure 5 shows a large placebo effect at week 12,
typical of any new intervention to treat behavioural and
psychiatric symptoms in dementia, especially when
outcome data are collected via a caregiver interview such as
NPI. This improvement is transient, unlike the continuous
improvement seen until the end of the treatment period in
the rivastigmine treated group. A corresponding placebo
effect is not seen in the CDR data (figure 2), which does
not require caregiver input. Closely similar results were
seen on other measures of efficacy, with the exception of
the incongruent Stroop test, which still showed a significant
advantage for the rivastigmine cohort at week 23.
Discussion
In our study, rivastigmine at daily doses of 6–12 mg
produced significant and clinically relevant behavioural
effects in Lewy-body dementia. Patients given rivastigmine
were less apathetic and anxious, and had fewer delusions
and hallucinations than those on placebo. In some patients
improvements were substantial. Objective measures of
cognitive functioning, especially attention and memory,
also showed striking improvement. Effects were
symptomatic and reversed on drug withdrawal.
Rivastigmine in dementia with Lewy-bodies seems safe and
well tolerated if titrated individually.
The psychiatric feature that improved most on
rivastigmine-treated patients was apathy and indifference,
followed by anxiety, delusions, and hallucinations.
Improvements in impaired attention, unresponsiveness,
and daytime somnolence—the core features of Lewy-body
dementia—were substantial. Similarly, hallucinations and
psychotic features resolved almost completely in over half
the patients on rivastigmine, with symptoms re-emerging
rapidly during the 3-week discontinuation period. The
2 Rivastigmine
Placebo
Mean change from baseline (NPI-4)
1
Deterioration
0 in mortality risk. Anti-parkinsonian medication given to
⫺1
⫺2
⫺3
Improvement
⫺4
⫺5
⫺6
⫺7
Baseline Week 12
Treatment phase
Figure 5: NPI-4 follow-up data set: mean changes (95% CIs)
from baseline
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
ARTICLES
minor differences seen in hallucination rates pretreatment
are unlikely to account for this finding, and the two groups
had similar exposure to relevant, concomitant
medications—ie, dopaminergics and psychotropics.
Improvements in psychiatric and behavioural features
were mirrored by changes in cognitive performance,
assessed by both computerised and paper-and-pencil tests.
Patients could complete the computerised tests, especially
those with a substantial attentional component,
significantly faster than those on placebo. Rivastigmine
offset the deterioration occurring on placebo, but also
actually improved patient performance to above baseline.
Accuracy scores also increased. The clinical relevance of
these improvements in attention was captured in caregiver
reports of patients, describing them as more alert and
switched on, and emphasised by reduced apathy scores on
NPI. 3 weeks after discontinuation of treatment, most of
the beneficial effect of rivastigmine was lost, suggesting that
the drug had a pronounced effect on symptoms but did not
reverse the course of the disorder. Serious adverse events
did not differ between the groups, and the profile was
similar to that seen with the drug in Alzheimer’s disease14,15
and to that reported for other cholinesterase inhibitors.
Rivastigmine was not associated with any clinically relevant
change in laboratory tests, vital signs, or electrocardiogram
results. Parkinsonian symptoms measured by the UPDRS
did not worsen on treatment, though emergent tremor was
noted as an adverse event in four rivastigmine-treatment
patients. As seen with other cholinesterase inhibitors, a
larger proportion of patients lost weight in the rivastigmine
group than with placebo.
There were more premature discontinuations in the
rivastigmine group than in placebo. This, together with the
higher incidence of gastrointestinal side-effects (nausea,
vomiting, and anorexia) seen in rivastigmine-treated
patients, could be related partly to the strategy of increasing
the dose every 2 weeks in the first 8 weeks up to the highest
tolerated level. Benefits of individual dose titration with
cholinesterase inhibitors are now well established.25
Additionally, prolonging the intervals between dose
increases has been shown to be associated with improved
tolerability for rivastigmine26 and for this class of drugs in
general. Thus, our results accord with and extend the
findings in previous case reports and open-label treatment
studies with cholinesterase inhibitors.9–11
Dementia with Lewy bodies is a common disorder that
poses difficult dilemmas in pharmacological management.
Treatment of psychiatric symptoms with antipsychotics not
only worsens extrapyramidal features but, in about half of
Lewy-body dementia patients exposed, can trigger severe
neuroleptic sensitivity reactions with a substantial increase
improve motor symptoms can, correspondingly, exacerbate
halluciniations and confusion. Extensive deficits in
neocortical cholinergic function occur in Lewy-body
dementia and are correlated with cognitive and psychiatric
symptoms. They are probably secondary to presynaptic
depletion in brain stem and basal forebrain cholinergic
nuclei, with more preservation of postsynaptic mechanisms
than seen in Alzheimer’s disease. These differences in
pathophysiology could explain why, in comparison with
the beneficial effects seen in Alzheimer’s disease, patients
with dementia showed even greater improvement in
cognition and neuropsychiatric symptoms when treated
Week 20 Week 23 with rivastigmine. A procholinergic treatment might
theoretically be predicted to exacerbate parkinsonism, but
Follow-up
in practice this effect does not seem to be common,
probably indicative of the complex interactions of non-
muscarinic, nicotinic cholinergic receptor mechanisms in
2035
ARTICLES
the control of basal ganglia function. Future studies of
cholinesterase inhibitors in dementia with Lewy bodies
should determine whether parkinsonism, particularly
tremor, emerges with higher dosing. The profile of
treatment responsive target symptoms needs to be fully
characterised and the impact of treatment upon cognitive
fluctuation, activities of daily living, and quality of life
should be quantified. Our study was exploratory in nature
and aimed at investigating the efficacy of rivastigmine in
Lewy-body dementia, which is clearly shown by our results.
The findings are to be interpreted descriptively and can be
used as a basis to design appropriately-powered trials in the
future in this population.
Therapeutic targeting of the cholinergic system in Lewy-
body dementia has the potential to avoid unwanted effects
predominantly mediated via dopaminergic systems. Our
study results suggest that cholinesterase inhibitors could be
a more rational choice of treatment for Lewy-body
dementia patients than neuroleptics, both on an efficacy
and safety basis. Reservations about the scarce effects of
cholinesterase inhibitors in the management of dementia
might be in part due to their use in patients with pure
Alzheimer’s disease and without clinically significant
neuropsychiatric symptoms, thereby excluding both
treatment-responsive target disease and symptoms.
Contributors
Data collection and comments on study design were made by the
International Exelon Investigators. Ian McKeith was the principal
investigator involved in the design and execution of the study, data
interpretation, and discussion of study results. Teodoro Del Ser was the
lead investigator in Spain and participated in study design and discussion of
findings. Pier’ Franco Spano stimulated initiation of the study and
contributed to all pharmacological aspects. Murat Emre contributed to
study design and selection of outcome measures. Keith Wesnes was in
charge of the computerised cognitive and neuropsychological tests,
including study planning, collection, analysis, and interpretation of results.
Ravi Anand, Novartis International clinical leader of Exelon, was involved
in supervising the study. Ana Cicin-Sain, Novartis clinical trial leader, was
responsible for coordinating, running, and supervising the study from the
medical side. Roberto Ferrara was the project statistician and contributed to
designing the protocol, and analysing and interpreting the results. René
Spiegel was involved in analysing and interpreting the results, and in writing
the paper.
Acknowledgments
We thank the following investigators: R Blesa, M Aguilar, J Peña,
F Bermejo, A Robles, Z Walker, G Livingston, J Waite, R Bullock,
D Wilkinson, E J Byrne, M Rosser, J Grace, U Bonuccelli, G Nordera,
A Polleri, L Ravizza, E Smeraldi, Pr Scarone, V Volterra; and S Vincent,
L Galiano, and R Turrini for coordinating the study; and Lucy Kanan and
Maureen Middlemist for producing the manuscript.
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THE LANCET • Vol 356 • December 16, 2000