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ARTICLES: L. B. Krupp, C. Christodoulou, P. Melville, W. F. Scherl, W. S. MacAllister, and L. E. Elkins Donepezil improved memory in multiple sclerosis in a randomized clinical trial Neurology 2004; 63: 1579-1585 [Abstract] [Full text] [PDF]

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Reply to Tsao et al

Lauren B Krupp, Christopher Christodoulou, Patricia Melville, William S. MacAllister, William F. Scherl, Leigh E Elkins   (27 January 2005)

Donepezil improved memory in multiple sclerosis in a randomized clinical trial

Jack W Tsao, Kenneth M. Heilman, MD, Gainesville, FL   (27 January 2005)

Reply to Tsao et al 27 January 2005
Lauren B Krupp, Department of Neurology, SUNY Stonybrook HSC T 12 020 SUNY at Stony Brook, Stony Brook. New York 11794-8121, Christopher Christodoulou, Patricia Melville, William S. MacAllister, William F. Scherl, Leigh E Elkins Send Correspondence to journal: Re: Reply to Tsao et al lauren.krupp{at}stonybrook.edu Lauren B Krupp, et al.	We thank Drs. Tsao and Heilman for their thoughtful comments regarding the effects of anticholinergic medications for bladder dysfunction. While our study was not specifically designed or powered to answer their questions, we have attempted to do so below. [1] It is difficult to distinguish the specific role of the bladder medications from the role of overall disease severity, since use of such medications increases with overall disease severity (e.g., MS type, EDSS). We found secondary progressive (SP) MS subjects more likely to use them than those with milder relapsing remitting (RR) disease; (75% vs. 32%; p = .002). Previous studies have found that SP patients display greater cognitive impairment than RR patients. [1,2,3] 1. The anticholinergic bladder agents used by the MS subjects were oxybutyrnin (n = 8) and tolterone (n = 7). One subject was on both. 2. The baseline selective reminding test (SRT) (the primary outcome measure of memory) scores for those on bladder medications did not differ from those not taking them (mean difference, 3.36; p = .184). Controlling for differences in disease severity (EDSS, MS type) lessened any apparent difference (excluded 3 PP subjects, none on bladder medications) (mean difference, 1.39; p = .608). 3. Only six subjects among the 35 in the donepezil group were on anticholinergic bladder medications. These six showed a trend toward more SRT improvement than the other 29 (mean difference, 6.75; p = .096). The trend was eliminated after controlling for baseline EDSS and MS type (excluded 2 PP subjects) (mean difference, 5.80; p = .234). 4. Excluding the 16 subjects on the bladder medications, a t-test comparing donepezil and placebo on SRT change found no difference (mean difference, 2.21; p = .286). We also repeated the analysis of treatment effect in this smaller sample, controlling for the same variables as in our paper (gender, MS type, EDSS, SRT baseline score, interferon beta therapy) (excluded the 3 PP subjects). We found a trend favoring a beneficial treatment effect for donepezil (mean difference, 4.17; p = .061) and the magnitude of this group difference was similar to that in the overall sample. These findings suggest that the treatment effect in the subsample without bladder anticholinergic medications would have reached significance had the analysis been adequately powered. These findings support a benefit of donepezil over placebo in improving memory in MS which is not adequately explained by concurrent use of anticholinergic bladder medications. A larger study separating anticholinergic effects from MS severity is necessary. We are undertaking a larger, multicenter donepezil study and hope to be in a better position to examine some of these questions. References 1. Grossman M, Armstrong C, Onishi K et al. Patterns of cognitive impairment in relapsing-remitting and chronic progressive multiple sclerosis. Neuropsychiatry, Neuropsychol Behav Neurol 1994;7:194-210 2. Krupp LB, Christodoulou C, Melville P, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63: 1579-1585. 3. Huijbregts SC, Kalkers NF, de Sonneville LM, de Groot V, Reuling IE, Polman CH. Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS. Neurology 2004; 63: 335-339.
Donepezil improved memory in multiple sclerosis in a randomized clinical trial 27 January 2005
Jack W Tsao, Uniformed Services University 9211 Bardon Road, Bethesda, MD 20814-2858, Kenneth M. Heilman, MD, Gainesville, FL Send Correspondence to journal: Re: Donepezil improved memory in multiple sclerosis in a randomized clinical trial jacktsao{at}earthlink.net Jack W Tsao, et al.	Krupp et al reported that, in MS patients, the ability to learn and recall (declarative memory) could be improved with anticholinesterase treatment (donepezil). [1] However, ten subjects (29%) in the placebo control group and six subjects (17%) in the donepezil group were reported to have been taking bladder medications, which we presume included anticholinergic agents. We reported two patients who took the bladder medication tolterodine (Detrol) and developed an amnestic disorder which reversed upon discontinuation of the medication. [2,3] One of these patients also had hallucinations while taking tolterodine, but this symptom resolved after starting donepezil. [3] We posited that these patients’ declarative memory disorders and hallucinations might have been induced by a medication-induced (tolterodine-induced) reduction of cerebral acetylcholine. Given the inflammatory nature of MS, there is also the possibility that the cerebral blood-brain barrier was more porous to these medications, possibly leading to an increased CNS penetration of these anticholinergic agents. The resulting increase in the brain concentration of anticholinergic agents in these patients might have led to an increase in propensity for adverse cognitive effects and, thus, also a better response to anticholinesterase treatment. These results can be assessed with the data that Krupp and her associates [1] collected on their subjects. We are hopeful that these investigators could provide the following information or analyses: 1. The names of actual bladder agents their subjects were taking; 2. An analyses to determine if, prior to treatment with donepezil, the cognitive performance of their subjects who were taking bladder agents was significantly different from those not on these bladder agents. 3. Based upon our observations, we would predict a greater improvement in cognition with donepezil treatment in those subjects who were taking anticholinergic bladder medications when compared to those not on these bladder agents. 4. If these investigators excluded those subjects on bladder agents, and performed an analysis of the effects of donepezil treatment would there still be positive effects? We hope that the investigators will perform these analyses and submit the results to Neurology because in the absence of these results, neurologists will be unable to know if they are treating an iatrogenic disease that perhaps could be better be treated with discontinuing or altering the type of medication used to treat disorders such as urge incontinence. References 1. Krupp LB, Christodoulou C, Melville P, et al. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63: 1579-1585. 2. Womack KB and Heilman KM. Tolterodine and memory: dry but forgetful. Archives of Neurology 2003; 60: 771-773. 3. Tsao JW and Heilman KM. Transient Memory Impairment and Hallucinations Associated with Tolterodine Use. N Engl J Med 2003; 349: 2274-2275.