Tolterodine and Memory: Dry but Forgetful

OBSERVATION Tolterodine and Memory Dry but Forgetful

Kyle B. Womack, MD; Kenneth M. Heilman, MD

Background: Anticholinergic drugs are known to pro- month after discontinuing tolterodine therapy, this test duce or enhance cognitive deficits. Tolterodine tartrate was administered a second time using an alternative form is marketed as a bladder-selective anticholinergic drug and she showed marked improvement scoring above the that is reported to be free of significant cognitive ad- 75th percentile. verse effects. Conclusions: Tolterodine therapy caused cognitive dys- Objective: To describe a 46-year-old woman who function in our patient. It is possible that cognitive dys- had memory loss and abnormal memory test results function is a common result of tolterodine treatment, but that improved when she discontinued tolterodine in the absence of testing, remains undiagnosed. Alterna- therapy. tively, our patient may have had aberrant metabolism of this drug or an increased sensitivity as a result of incipi- Results: While taking tolterodine, the patient’s score on ent Alzheimer disease. the delayed free recall portion of the Hopkins Verbal Learning Test–Revised was at the first percentile. One Arch Neurol. 2003;60:771-773

EDICATIONS THAT block Specifically, she reported forgetting events muscarinic choliner- such as meetings at work as well as some gic transmission are outings with her family. She began hav- known to interfere with ing to write down everything at work, and learning and memory.1 reported particular difficulty remember- MPatients with Alzheimer disease (AD) have ing numbers. She also reported syntactic cholinergic deficits and have an in- errors in which word order was dis- creased sensitivity to cognitive adverse ef- turbed. Her medical history was notable fects from these agents.2 We examined a for anxiety, essential tremor, and urinary woman with memory impairment who was stress incontinence. Her medications at the being treated with tolterodine tartrate, a time of evaluation included a combina- muscarinic antagonist. The online Physi- tion of conjugated estrogens, 0.625 mg/d, cian’s Desk Reference3 listed no true cog- and medroxyprogesterone acetate, 5 mg/d; nitive adverse effects and no contraindi- venlafaxine hydrochloride, 150 mg/d; cations or precautions that pertain to the fexofenadine hydrochloride, 180 mg/d; use of tolterodine in cognitively impaired propranolol hydrochloride, 10 mg, three or elderly populations. Furthermore, a re- times daily; tolterodine tartrate, 4 mg/d view of the literature on tolterodine ar- (which had been started 3 months prior gues against significant cognitive adverse to this visit); and vitamin E, 800 IU/d. Her effects (other than a 2% incidence of diz- family history was positive for dementia From the Department of ziness and fatigue)4-10 and even promotes in her mother (mixed, AD and vascular de- Neurology, University of its use in older patients.11 When we dis- mentia), her maternal grandmother (type Florida College of Medicine, continued the use of this medication, how- unknown), and several maternal aunts and and the Neurology Service, ever, her memory improved. uncles (AD). During testing, the patient Department of Veterans Affairs appeared calm and put forth good effort. Medical Center, Gainesville. Dr Womack is now with the REPORT OF A CASE Mental status testing revealed a Mini- Departments of Neurology and Mental State Examination score of 30. Psychiatry, University of Texas A 46-year-old, right-handed woman re- Testing of attention revealed no distract- Southwestern Medical Center at ported decreased memory, which had be- ibility during visual field examination, a Dallas. come worse over the preceding 2 years. digit span of 7 forward, and normal per-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 formance on a letter cancellation task. Intention was also Despite what is known about the effect of antimus- intact with no evidence of impersistance on a sustained carinic drugs on memory and cognition, tolterodine does motor task, no evidence of bradykinesia, normal perfor- not carry specific warnings about true cognitive adverse mance on a contrasting programs paradigm, and a nor- effects or use in at-risk populations. The clinical trials mal score (39) on the controlled word association test12 leading to Food and Drug Administration approval of for letters /F/,/A/, and /S/. The Boston Naming Test13 was tolterodine relied primarily on spontaneous reports of ad- given and she scored 56 of 60, which is normal. Her spon- verse events for dry mouth, and detailed cognitive test- taneous speech was fluent with normal pace, word quan- ing was not done.4,7 Another muscarinic antagonist, oxy- tity, grammar, and articulation. Repetition and compre- butynin chloride, likewise carried no warnings of cognitive hension were intact. There was no ideomotor apraxia. adverse effects (except for dizziness and somnolence)18 Finger naming was intact and there was no right-left con- but was later shown to cause a decline in 7 of 15 cogni- fusion. Because of her report of impaired memory, we tive measurements in healthy elderly subjects.19 administered the Hopkins Verbal Learning Test– It has been argued that tolterodine would be less Revised (form 3)14 where she was presented a list of 12 likely to cause cognitive deficits than oxybutynin be- words on 3 sequential trials. After each trial her imme- cause oxybutynin caused significant changes in the quan- diate recall of these words was assessed. She performed titative electroencephalographic power spectrum while well on the learning and immediate free recall test with tolterodine produced only a slight power reduction within a combined score of 30 of 36 (50th-75th percentile), which the theta frequency band.20 Such measurements, how- is in the normal range. On delayed free recall, however, ever, may not fully predict if an agent can induce amne- she remembered only 5 of 12 words (first percentile), sia. Another argument cites the relatively low pen- which is abnormal, and had one semantically related in- etrance across the blood-brain barrier of tolterodine and trusion. In contrast, her delayed recognition was good, its metabolites as measured in mice21 and as suggested recognizing 12 of 12 with no false-positive results. Find- by the lipophilicity of the active compounds. Toltero- ings from the remainder of her neurological examina- dine is more than 30 times less lipophilic than oxybu- tion showed no abnormalities. Values from laboratory tynin. The active 5-hydroxymethyl metabolite, which is studies including a magentic resonance image of her head, the predominant species in extensive metabolizers, is more free thyroxine, thyrotropin, treponemal antibody test, vi- than 350 times less lipophilic than oxybutynin.22 tamin B12, methylmalonic acid, folate, and erythrocyte Despite those arguments, there are at least 3 rea- sedimentation rate were normal. We recommended that sons that, alone or in combination, may explain why our she increase her dose of vitamin E up to 2000 IU/d and patient suffered memory problems secondary to toltero- discontinue tolterodine therapy. We saw her in fol- dine therapy. First, since the effect on memory in hu- low-up 1 month later and she reported improvement in mans has not been directly studied, perhaps memory im- her memory and no further syntactic errors. A second pairment is a common but heretofore undocumented testing with the Hopkins Verbal Learning Test–Revised adverse effect of tolterodine. Second, our patient may have (form 2), which is equivalent to form 3 for recall and has been one of the 7% of the population, who lack the good test-retest reliability,14 revealed an immediate free CYP2D6 enzyme that converts tolterodine to the 5-hy- recall score of 33 of 36 and a perfect delayed free recall droxymethyl metabolite.3 In these poor metabolizers, the of 12 of 12 (Ն75th percentile). more lipophilic parent compound predominates, result- ing in the likelihood of greater central nervous system COMMENT penetration. Third, she may have had an unusual sensitivity to antimuscarinic medications, which is interest- Scopolamine, a prototypic antimuscarinic drug, is known ing in light of the known increased sensitivity seen in AD.2 to impair verbal learning, to severely impair delayed free Ever since Sunderland et al2 demonstrated this in- recall, and to have only minor or no effect on recogni- creased sensitivity to scopolamine in patients with AD, tion recall for items learned under its influence. Addi- there has been speculation about the possibility of de- tionally, it has little or no effect on immediate recall as tecting a preclinical phase of AD by evaluating asymp- tested by digit span.15-17 tomatic individuals for increased anticholinergic sensi- While our patient had normal verbal learning, her se- tivity.23 Although one small study looked at this verely impaired delayed free recall with normal recogni- prospectively with negative results24 and another study25 tion and a normal digit span is consistent with the ex- has argued that the cholinergic degeneration may occur pected deficits from an anticholinergic medication. The later in the course of AD than previously thought, the resolution of her free recall deficit when tolterodine therapy question remains open. Our patient’s strong family his- was discontinued further supports the causal role of this tory of AD makes this possibility particularly salient. In medication. The patient’s memory impairment began prior addition to impaired free recall, patients with AD typi- to the initiation of tolterodine therapy suggesting that her cally have deficits of recognition recall,26,27 which our pa- memory deficit could not be solely due to this medica- tient did not have. If preclinical changes, however, merely tion. Nevertheless, in the absence of tolterodine therapy, increase the susceptibility to anticholinergic drugs, then results from the patient’s memory testing were normal and the pattern of deficits would be expected to be consis- any underlying diagnosis remained obscure in the ab- tent with these drugs rather than with AD. Additionally, sence of objective deficits. The relationship of her re- one study that looked at healthy, very elderly subjects ported language disturbance to tolterodine was unclear since with no dementia found that those who later developed we had no objective documentation of this report. AD had performed worse on recall and no differently on

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 recognition than the members of their cohort who re- 7. Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than mained free of dementia.28 and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol. 2001;165:1452-1456. Studies are needed to directly examine the cogni- 8. Millard R, Tuttle J, Moore K, et al. Clinical efficacy and safety of tolterodine com- tive effect of tolterodine therapy on young as well as el- pared to placebo in detrusor overactivity. J Urol. 1999;161:1551-1555. derly populations using neuropsychological instru- 9. Nilvebrant L, Andersson KE, Gillberg PG, Stahl M, Sparf B. Tolterodine–a new ments. Correlation with metabolic type, age, and risk bladder-selective antimuscarinic agent. Eur J Pharmacol. 1997;327:195-207. factors for AD (apolipoprotein E genotype, family his- 10. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A. Tolterodine once- daily: superior efficacy and tolerability in the treatment of the overactive blad- tory) could identify groups at particular risk for the cog- der. Urology. 2001;57:414-421. nitive adverse effects of tolterodine to note whether a gen- 11. Malone-Lee JG, Walsh JB, Maugourd MF. Tolterodine: a safe and effective treat- eral risk exists. Additionally, we could also learn if ment for older patients with overactive bladder. J Am Geriatr Soc. 2001;49:700- increased sensitivity to drugs like tolterodine might be 705. indicative of incipient AD. 12. Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuro- psychologia. 1967;5:135-140. Given the aging population and the direct market- 13. Kaplan E, Goodglass H, Weintraub S. Boston Naming Test. Philadelphia, Pa: Lea ing of this drug through television advertisements, more & Febiger; 1983. information is needed to prevent avoidable adverse ef- 14. Benedict RH, Schretien D, Groninger L, Brandt J. Hopkins Verbal Learning Test– fects and to recognize them when they occur. In addi- Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol. 1998;12:43-55. tion to raising suspicions about the safety profile of toltero- 15. Hasselmo ME, Wyble BP. Free recall and recognition in a network model of the dine, this case also illustrates the use of detailed mental hippocampus: simulating effects of scopolamine on human memory function. status testing. A screening test such as the Mini-Mental Behav Brain Res. 1997;89:1-34. State Examination, which has limitations because of ceil- 16. Ghoneim MM, Mewaldt SP. Effects of diazepam and scopolamine on storage, ing effects,29,30 would have missed an identifiable prob- retrieval and organizational processes in memory. Psychopharmacologia. 1975; 44:257-262. lem that, in this case, was treatable. 17. Beatty WW, Butters N, Janowsky DS. Patterns of memory failure after scopolamine treatment: implications for cholinergic hypotheses of dementia. Behav Neu- Accepted for publication August 23, 2002. ral Biol. 1986;45:196-211. Author contributions: Study concept and design (Drs 18. Entry for Ditropan XL (Alza) (oxybutynin chloride) extended release tablets. Avail- Womack and Heilman); acquisition of data (Dr Wom- able at: http://physician.pdr.net. Accessed August 15, 2002. 19. Katz IR, Sands LP, Bilker W, et al. Identification of medications that cause cog- ack); analysis and interpretation of data (Drs Womack and nitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Heilman); drafting of the manuscript (Dr Womack); criti- Soc. 1998;46:8-13. cal revision of the manuscript for important intellectual con- 20. Todorova A, Vonderheid-Guth B, Dimpfel W. Effects of tolterodine, trospium chlo- tent (Dr Heilman); administrative, technical, and mate- ride, and oxybutynin on the central nervous system. J Clin Pharmacol. 2001;41: rial support (Dr Womack); study supervision (Dr Heilman). 636-644. 21. Pahlman I, d’Argy R, Nilvebrant L. Tissue distribution of tolterodine, a musca- This study was supported in part by a grant from the rinic receptor antagonist, and transfer into fetus and milk in mice. Arzneimittel- State of Florida, Department of Elder Affairs, Tallahassee. forschung. 2001;51:125-133. Corresponding author: Kyle B. Womack, MD, Univer- 22. Nilvebrant L. Clinical experiences with tolterodine. Life Sci. 2001;68:2549- sity of Texas Southwestern Medical Center at Dallas, 5323 2556. 23. Pomara N, Nolan K, Halpern G. 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