Alcohol and Alcoholism Advance Access originally published online on November 5, 2007
Alcohol and Alcoholism 2008 43(1):70-72; doi:10.1093/alcalc/agm158
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Case Report
Rivastigmine in Wernicke-Korsakoff's syndrome: Five patients with rivastigmine showed no more improvement than five patients without rivastigmine
1 Parnassia Groep, The Hague, The Netherlands
2 Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
3 Department of Research ParnassiaGroep, The Hague, The Netherlands
4 Parnassia Addiction Research Centre, The Hague, The Netherlands
* Author to whom correspondence should be addressed at: Parnassia-Medical Center, Jan Hein Donnerstraat 53, 2553 RZ The Hague, The Netherlands. Tel: (+003) 170 391 6900; Fax: (003) 170 391 6369; E-mail: luykxj{at}parnassia.nl
Received 26 October 2006; first review notified 1 December 2006; in revised form 6 July 2007; accepted 2 October 2007
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ABSTRACT |
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 TOP ABSTRACT IntroductionMethodsData AnalysisResultsDiscussionConflicts of InterestReferences |
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Aims: To evaluate whether rivastigmine, an achetylcholinesterase inhibitor (AChEl), may be effective in restoring memory in Wernicke-Korsakoff's syndrome (WKS). Methods: Five patients treated with rivastigmine for a period of 6 months were compared with five matched control patients, who received 6 months' conventional treatment, but without rivastigmine. Memory tests were administered at baseline and after 6 months. Results: Slight improvements were observed in both rivastigmine and control patients, but no significant differences in improvements were found between the study groups. Conclusion: Treatment with rivastigmine may not be effective in restoring memory in WKS patients.
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Introduction |
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TOPABSTRACTIntroductionMethodsData AnalysisResultsDiscussionConflicts of InterestReferences |
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Since 2001, case studies have reported on the beneficial effect of acetyl cholinesterase inhibitors (AChEl's) in the persisting amnestic syndrome or Wernicke-Korsakoff's syndrome (WKS) (Cochrane et al., 2005
). On the contrary, one small and placebo-controlled cross-over study showed no improvement in memory after treatment with donezepil, an AChEl, in WKS caused by hunger pangs (Sahin et al., 2002). Clinically, the Korsakoff part of the WKS is characterized by a persistent anteretrograde episodic memory loss, while semantic memory, intelligence, and learned behaviour are preserved (Kopelman, 1995). As Wernicke's syndrome, WKS is caused by thiamine deficiency. In a study, neurodegeneration of the hypothalamic mamillary nuclei and the mediodorsal thalamic nuclei appeared substantial in both Wernicke's syndrome and WKS (Harding et al., 2000). However, neuronal loss of the anterior thalamic nuclei was found consistently only in WKS (Harding et al., 2000). The anterior nuclei of the thalamus are considered to be an integral part of the ‘extended hippocampal system’ (Aggleton and Saunders, 1997).
The cholinergic system plays a dominant role in the modulation of the activity of the cortex, thalamus, and hippocampus (Perry et al., 1999). The cholinergic system projects from groups of cells in the forebrain (nucleus basalis of Meynert) and the brainstem (pedunculopontine neurones) to the cortex, thalamus, and hippocampus (Perry et al., 1999). The projection from the nucleus basalis modulates selective attention. Together, these cholinergic cell groups modulate consciousness, waking, and REM sleep by synchronizing cortical activity (Perry et al., 1999).
In rats, persistent memory loss induced by alcohol is associated with loss of cholinergic forebrain cells and cholinergic dysfunction of the cortex and the hippocampus. No histological changes of the thalamus were found (Arendt et al., 1988), whereas such changes are apparent in humans. In rats, the memory impairment could be restored by placing fetal cholinergic implants in the cortex or the hippocampus (Arendt et al., 1988), or by supplying a cholinergic drug (Hodges et al., 1991). On the basis of these findings it was concluded that acetylcholine (ACh) plays a key role in the alcohol-induced loss of memory in rodents. In humans, cholinergic blockade causes a memory impairment as observed in Alzheimer's disease and in WKS (Kopelman and Corn, 1988). However, a study comparing clinical and pathological anatomical states revealed only a similar and moderate loss of the ACh producing nucleus basalis of Meynert in Wernicke's syndrome as well as in the combined WKS (Cullen et al., 1997). From this study it can be concluded that ACh deficiency in WKS is non-specific and limited in degree.
Moreover, it has been suggested that a relative deficiency of ACh does not primarily cause a memory impairment but rather a state characterized by impairment of attention and concentration, anxiety, restlessness, and hallucinations (Lemstra et al., 2003). So, the basis for an ACh deficiency in the WKS is questionable. Given these inconsistent findings, we tested the hypothesis that increased availability of ACh by rivastigmine, an AChEl, can improve alcohol-induced memory impairment in WKS, using a matched control design.
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Methods |
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Five WKS patients were consecutively selected from the department for Korsakoff's patients from a psycho-medical centre in The Hague, The Netherlands. Four of these patients were recently admitted for diagnostic reasons; one patient was living in a Korsakoff home for 18 months. The diagnosis of WKS was firmly based on a history of severe drinking and a non-progressive mental condition of a persisting amnestic syndrome without another symptom indicative of dementia. Eligibility criteria consisted of (i) good physical health, (ii) no contra-indication for the use of rivastigmine, (iii) abstinence from alcohol for at least 2 months, and (iv) meeting the DSM-IV diagnostic criteria (American Psychiatric Association, 2000
) for the persisting amnestic syndrome by alcohol. The patients received rivastigmine in the following scheme: 1.5 mg 2 times a day in the first and second weeks, 3 mg 2 times a day in the third and fourth weeks, 4.5 mg 2 times a day in the fifth and sixth weeks, and 6 mg 2 times a day from the seventh week, and intentionally until the end of the trial. The treatment was supplied during 6 months analogous to the AChEl trials in Alzheimer's disease. This experimental group was compared with a group of five patients from the same department, selected by the same criteria. The control group was matched with the experimental group in respect to gender (all male), age (median age being 46 years in the experimental group versus 47 years in the control group), time of abstinence (at least 2 months), psychotropic co-medication, and recent institutionalization. They did not receive rivastigmine, and followed the same treatment regime as the experimental group of patients.
Memory testing was conducted at baseline (i.e. before treatment) and after 6 months. Both groups were assessed with instruments that are generally regarded as specific for memory disturbances: a visual memory task, analogue to the Auditory-Verbal Learning Test (AVLT) (Lezac et al., 2004), called the ‘Word Image Learning Test’, the Verbal Fluency Test (Lezac et al., 2004), a verbal memory test, and the AVLT, mentioned above. One experienced psychology assistant administered the tests.
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Data Analysis |
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Differences between the two study groups in pre- to post-treatment patient changes on the various scales were analyzed by means of a 2 x 2 mixed design repeated measurement Analysis of variance (ANOVA) for Group (rivastigmine versus control) x Time (pre-treatment vs post-treatment).
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Results |
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All five patients of the medication group completed the 6-months treatment period of rivastigmine. Four patients tolerated the maximum daily dose of 12 mg, and one patient developed bradycardia. Consequently, the dose in this patient was reduced to 6 mg a day. All five patients of the control group completed the 6-month normal treatment regime.
For group, main effects were found for the scales ‘Free Recall’ [F(1, 8 = 6.64; P = 0.033] and ‘Delayed recall’ [F(1, 8) = 7.96; P = 0.022] of the Word Image Learning Test (Table 1). In addition, main Time effects were found for ‘Free recall’ [F(1, 8) = 92.56; P = 0.000] and ‘Delayed recall’ [F(1, 8) = 11.54; P = 0.009]. Although statistically significant, the post-treatment values remained far below the normal values found for ‘free recall’ (9.3) and ‘delayed recall’ (9.8). No significant main effects were observed on any of the other scales. Furthermore, no significant Group x Time interaction effects were observed on any of the scales. Hence, no significant differences in pre- to post-treatment patient changes on the memory scales were found between the two study groups (Table 1).
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Discussion |
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TOPABSTRACTIntroductionMethodsData AnalysisResultsDiscussionConflicts of InterestReferences |
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In this study, the effect of treatment with rivastigmine on memory in WKS patients was evaluated in ten patients. The results showed slight improvements in patients who received rivastigmine, and in control patients on visual short-term memory and learning capability (free recall), as well as on consolidation (delayed recall). No other improvement was found in these patients. Therefore, this change was validated as the result of the 6 months of abstinence, and as clinically insignificant.
In conclusion, this study did not find a positive effect of rivastigmine. Hence, treatment with rivastigmine may not be effective in restoring memory in WKS patients. The result can be seen as in line with the Cullen study (Cullen et al., 1997) and as confirmation of the controlled Sahin trial (Sahin et al., 2002). Although the pathogenesis of the serious memory disturbance in WKS is not fully unravelled, it is hypothesized that the lack of ACh is not a decisive feature of the WKS, contrary to the situation of the alcohol-induced memory disturbance in rodents.
Limitations
First, the study may have been limited by the small sample size. Nevertheless, although no significant interaction effects were found which obviously constitute the critical outcome of this study, significant main effects did occur, even in this small sample. Second, all patients in the present study had a severe amnestic syndrome, with possible serious structural damage in the thalamus. Therapy with rivastigmine may not be effective in this group, whereas patients with less severe forms of WKS may have benefitted from it.
Further studies, for example, pharmacological functional magnetic resonance imaging (MRI), could clarify the possible effect of an AChEI in the WKS.
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Conflicts of Interest |
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TOPABSTRACTIntroductionMethodsData AnalysisResultsDiscussionConflicts of InterestReferences |
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Disclosure: The authors have reported no conflicts of interest. NOVARTIS Pharmaceuticals Inc. provided rivastigmine.
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References |
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Aggleton J. P., Saunders R. C. The relationships between temporal lobe and diencephalic structures implicated in anterograde amnesia. Memory (1997) 5:49–71.[Web of Science][Medline]
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (2000) 4th edn. 513–517. text revision, 739–740.
Arendt T., Allen Y., Sinden J., et al. Cholinergic-rich brain transplants reverse alcohol-induced memory deficits. Nature (1988) 332(6163):448–450.[CrossRef][Medline]
Cochrane M., Cochrane A., Jauhar P., et al. Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome–three further cases show response to donepezil. Alcohol and Alcoholism (2005) 40(2):151–154.
Cullen K. M., Halliday G. M., Caine D., et al. The nucleus basalis (Ch4) in the alcoholic Wernicke-Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients. Journal of Neurology, Neurosurgery and Psychiatry (1997) 63(3):315–320.
Harding A., Halliday G., Caine D., et al. Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain (2000) 123:141–154. Pt 1.
Hodges H., Allen Y., Sinden J., et al. The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats. Behavioural Brain Research (1991) 43(1):7–28.[Web of Science][Medline]
Kopelman M. D. The Korsakoff syndrome. British Journal of Psychiatry (1995) 236:315–330.
Kopelman M. D., Corn T. H. Cholinergic ‘blockade’ as a model for cholinergic depletion. A comparison of the memory deficits with those of Alzheimer-type dementia and the alcoholic Korsakoff syndrome. Brain (1988) 111:1079–1110. Pt 5.
Lemstra A. W., Eikelenboom P., van Gool W. A. The cholinergic deficiency syndrome and its therapeutic implications. Gerontology (2003) 49(1):55–60.[CrossRef][Web of Science][Medline]
Lezac M. D., Jowleson D. B., Loring D. W. Neuropsychological Assessement (2004) 4th edn.
Perry E., Walker M., Grace J., et al. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends in Neurosciences (1999) 22(6):273–280.[CrossRef][Web of Science][Medline]
Sahin H. A., Gurvit I. H., Bilgic B., et al. Therapeutic effects of an acetylcholinesterase inhibitor (donepezil) on memory in Wernicke-Korsakoff's disease. Clinical Neuropharmacology (2002) 25(1):16–20.[CrossRef][Web of Science][Medline]
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