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THERAPEUTIC EFFECTS OF AN ACETYLCHOLINESTERASE INHIBITOR
(DONEPEZIL) ON MEMORY IN WERNICKE-KORSAKOFF’S DISEASE Hüseyin
A. Þahin, M.D. Ýstanbul
University, Ýstanbul Medical School, Department of Neurology, Address
correspondence and reprints: Key
Word: Wernicke Korsakoff’s disease, cholinesterase-inhibitors, memory. Abstract
Objective- Wernicke-Korsakoff’s
Disease (WKD) is cognitively an amnestic state resulting from strategic lesions in the
limbic system subserving episodic memory network, due to thiamine deficiency.
Neurochemical deficits have been implicated in the pathophysiology of amnesia based on the
pathologic observations that various brainstem and basal forebrain nuclei are also
affected. Previous treatment attemps with serotoninergic, noradrenergic and cholinergic drugs gave controversial results. The
objective of this study was to assess the effects of a cholinesterase inhibitor,
donepezil, on memory, attention and executive functions of patients with non-alcoholic
WKD. Methods- Seven
patients who developed WKD following a hunger-strike were included in this single-blind,
placebo-controlled, cross over study. The
patients were given donepezil during the first 30, and placebo during the following 30
days. Neuropsychological tests to evaluate verbal and visual memory, attention and executive functions were performed on days 0, 31
and 61. Results- All
patients completed the both phases of the study. There were no statistically significant
differences between the three evaluations, except for a difference between active
treatment and placebo phase in recall of Rey-Osterrieth Complex Figure, which was in
favour of the placebo phase. Three were no statistically different changes in favor of the
active treatment Conclusions- Cholinergic treatment with
cholinesterase-inhibitors does not seem to be effective in WKD. This may be because
pathways mediating both channel and state dependent functions are impaired in this
disease, and enhancement of state-dependent cholinergic transmission may not be
sufficient. INTRODUCTION
Wernicke-Korsakoff’s Disease
(WKD) is cognitively a pure amnestic state that is related to thiamine depletion1. Corpus mamillare (CM), dorsomedial nucleus of
thalamus (DM) and periaquaductal gray matter are the major neural structures that are
involved in the disease process1,2,3. First
two structures are considered to be responsible for amnesia, since they are the basic
relay stations on the two parallel pathways connecting hippocampus and amygdala with other
structures of episodic memory neural network4,5,6,7,8. Lesions in the ascending
neurotransmitter nuclei, i.e. noradrenergic locus ceruleus, serotonergic dorsal raphe
nucleus and cholinergic basal nucleus of Meynert, are also noted9,10,11,12,13,14,15.
The rationale for pharmacological intervention in WKD, via manipulation of different
neurotransmitter systems is largely based on the latter pathologic observations11,12,13,16. In the past there have been a number of
controversial reports regarding the beneficial effects of monoaminergic treatments10,12,16,17. Despite the implication of nucleus basalis of
Meynert in the pathophysiology, to our knowledge, there have been only two reported
studies on the use of cholinergic agents in alcoholic WKD, and none in non-alcoholic WKD18,19.
In the present study we assessed the therapeutic effects of an acetylcholinesterase
inhibitor(AchE-I), donepezil on memory,
attention and executive functions of patients with non-alcoholic WKD. METHODS Patients Seven patients with the
diagnosis of WKD were included in the study. All patients were under our care since the
beginning of their illness in 1996. They were all suffering from the consequences of a
69-day-mass scale hunger strike. Forty of the survivors had a cerebellar syndrome
(nystagmus, ataxia) compatible with the sequel of Wernicke’s Encephalopathy, seven of
whom had an additional amnestic state. The
latter group was labelled as WKD. This group
was among the 18 hunger strikers, who were referred to our care for a 3 to 6 week-hospital
stay immediately after the termination of the strike. Clinical characteristics of patients
was shown on Table 1. Despite the variable
degree of improvement in cerebellar signs, amnesia was largely stable over the ensuing 3
years. All seven patients were male
with a mean age of 31 years (range 27-39). Four
of them were mildly ataxic and required no assistance in walking, 2 had moderate ataxia
and were in need of walkers, and last one had severe ataxia, being practically
wheelchair-bound. Five of them had psychotic
episodes during the follow-up period. The episodes always had a depressive character
accompanied with fantastic paranoid delusions. Two had single episodes, one in the 2nd
month, one in 2nd year after the hunger strike The former was markedly
apathetic and the latter was psychiatrically symptom-free
during the present study. Three had recurrent psychotic episodes and showed
some residual paranoid ideation. The remaining two did not develop psychosis, but
displayed marked personality changes. One was apathetic, the other showed disinhibition
with inappropriate, childish behavior. The anterograde amnesia was
classified as moderate to severe in 6, and mild in one. After 3 years, they all remembered
that they had a hunger strike, they had some recollection of the medical team, but
temporal aspects of the retained information were virtually absent: “when and how long
was the hunger strike?”. A recently released patient could not answer whether he had
been free since a week or six months. Retrograde
component went several years back. One
patient identified himself as belonging to a political group which had already been
dissolved to merge into another one, some two years ago.
Another patient was telling how he had been surprised to see his 8-year old
son as a big child, everytime he came to visit him in prison, while all his memories about
him could not go beyond his infancy, how hard he had tried. Evaluations
A neuropsychological battery,
listed in Table 2 was used to assess the efficacy of cholinergic treatment20,21,22,23,24,25. Detailed neuropsychological assessments of
patients had already been performed with a comprehensive battery, acutely and 1-year
post-onset. The results had been presented
elsewhere26. Briefly, their
cognitive profile can be summarized as a stable, isolated amnestic state, where
linguistic, visuo-spatial and executive functions were well preserved. For the purpose of this study, a relatively brief
neuropsychological battery with an emphasis on amnestic functions was selected. The same test material was used in all three
sessions. After detailed explanation of the study, to the patients themselves and to the
caregivers, consents were obtained from the caregivers. In a single-blind, two-phased,
crossover design, a single morning dose of donepezil (5mg
for the first fifteen days, 10 mg thereafter)
was administered for 30 days, after which donepezil placebo was administered
for the same duration. Neuropsychological testing was performed on days 0, 31 and 61. The
three set of test scores at baseline, end of active treatment and end of placebo phase
were compared with each other using Friedman test. Statistically significant differences
were further analyzed with Wilcoxon-paried test in order to assess if the significance was
due to changes from baseline to the end of active treatment or to changes from baseline to
the end of placebo treatment.
RESULTS
All seven patients completed
both phases of the study as planned. They all tolerated the drug well and there were no
significant adverse events. None of the patients, neither the caregivers noted any
subjective improvement or worsening during the two phases of the treatment. Statistical analysis of neuropsychological test
scores across the three testing sessions using Friedman test revealed statistically
significant differences only for Camden topographical recognition memory test and
Rey-Osterrieth Complex Figure immediate and delayed recall (Table 3). Further analysis
using Wilcoxon’s paired-t test revealed, however, that the only significant difference
between active treatment and placebo phase was in Rey-Osterrieth Complex Figure. This
difference, however, was in favour of the placebo phase (Table 4). There were no other
statistically significant changes, particularly in favour of the active treatment, in any
other score. DISCUSSION
The central monoaminergic and
basal forebrain cholinergic pathways are vulnerable to disruption in WKD due to the
critical location of the classical lesions. McEntee
et al. found a decrease in 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels, a metabolite of
noradrenalin, in cerebrospinal fluid of patients
with WKS and noted a strong correlation between the decrease in CSF MHPG and the degree of
memory impairment9,10,11. This finding prompted the use of noradrenergic
substances in therapeutic trials. Mc Entee
and Mair reported favourable results with clonidine, an alpha-2 adrenergic agonist in two
separate studies. Measures of anterograde
memory function improved in both studies, but apparently the impact of this improvement on
activities of daily living (ADL’s) was negligible10,16. Mc Entee and Mair also reported decreased CSF
levels of 5-HIAA, the metabolite of serotonin11.
Based on this observation, Martin et al used fluvoxamine, a serotonin
reuptake inhibitor, in an attempt to treat the memory impairment. They found improvement on psychometric measures
including memory and attention, but there was no mention of ADL’s12. In two studies, Arendt et al., and Cullen et al.,
demonstrated reduced cell counts in the Nucleus basalis of Meynert (Ch4) in patients with
WKD14,15. There have been two reports on the therapeutic use of cholinergic agents in the patients. O’Donnell et al. reported on the use of
cholinergic precursor choline chloride and Franchesci et al. on AChE-I physostigmine, both without any beneficial effects18,19. This single blind, crossover,
placebo-controlled study failed to show any beneficial effects of donepezil treatment for
1 month on any of the cognitive parameters in patients with WKD, including verbal and
visual memory. In general, similar almost identical performances were obtained across the
three testing sessions within a two-month time period. Improvements on some measures were
largely insignificant and clinically irrelevant. It is now widely accepted that
the neural plasticity is essential for the
registration and storage of new information27,28. It is likely that
hippocampus, amygdala and connected limbic structures are necessary for learning and
recall of newly acquired information, whereas it seems that long term storage occurs in
the neocortex where the specific information had been processed, via plastic changes4,5,6.
Cholinergic innervation of the neocortex is thought
to be largely responsible for the long-term stability
of the memory traces. In our study AchE-I donepezil
failed to induce any beneficial effects on the memory of patients with WKD. This negative
result may be due to the fact that primary lesions which are responsible for amnesia in
WKD are on two critical structures of the episodic memory network2,3,4,5,6,7. These are hippocampus and amygdala-related
gateways or bottle-necks for access into the network27,28. As suggested by
Mesulam, cortico-cortical and cortico-subcortical monosynaptic reciprocal connections of a
neural network subserve its channel-dependent functions, which define the type of
information to be processed27. On the other hand, state-dependent functions are
subserved by diffuse projections from ascending neurochemical pathways to the network in
question. These modulate the intensity and enable the stability of the specific
information. Therefore, disruption of the former function is largely not amenable to
pharmacological intervention, whereas the latter is. Deficits due to territorial strokes
versus those in Parkinson’s disease are such examples, respectively27. Alzheimer’s disease, on the other hand, stands
on the midway between these two examples. Limbic
degeneration in AD disrupts both channel (hippocampus and amygdala) and state-dependent
(Nucleus basalis of Meynert) functions; cholinergic enhancement which has a modest yet
significant place in AD treatment, may work through improvement in state-dependent
functions. In WKS, however, where the core limbic damage is acute and complete, no new information can gain access
into the system in order to be processed and stabilised through cholinergic mediation27. In conclusion, cholinergic
treatment in WKD does not seem to improve memory function.
This may be due to the fact that, when channel-dependent functions fail
because of the disruption in the major relay
stations of the memory network, enhancement of state-dependent modifying inputs cannot
improve function28. Acknowledgement:
We would like to thank to Dr. Sevda Özel for statistical analysis and to Pfizer inc.,
Turkey for supplying the study drugs. REFERENCES 1. Victor M, Adams RA, Collins GH. The Wernicke-Korsakoff syndrome and related neurological disorders due to alcoholism and
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Korsakoff’s disease: pathologic and therapeutic implications. Prog. Clin. Biol. Res. 1981;71:211-23. 17. O’Carrol RE, Moffoot A, Ebmeier
KP, Murray C, Goodwin M. Korsakoff’s syndrome, cognition and clonidine. Psychological Medicine 1993;23:341-347. 18. Franchesci M, Tancredi O, Savio G,
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Table 2
Neuropsychological
Battery
Verbal Memory
California Verbal Learning Test20 Visual Memory
Rey-Ostherrieth
Complex Figure21
Camden Facial,
Pictorial and Topographical Recognition Tests 22 Attention
Digit Span23 Executive Functions
Trail Making Test A-B24 Stroop Test25 Controlled Oral Word
Association Test (K-A-S) Table 3
Results of the
Neuropsychological Evaluation
A: Baseline (mean±SD) B: Day 31 (mean±SD) C: Day 61(mean±SD) Table 4 Results of Wilcoxon
paired-t test
A: Baseline (mean±SD) B: Day 31 (mean±SD)
C: Day 61(mean ±SD)
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