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Mental confusion associated with scopolamine patch in elderly with mild cognitive impairment (MCI)
Archives of Gerontology and Geriatrics 49 (2009) 204–207
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Mental confusion associated with scopolamine patch in elderly with mild cognitive impairment (MCI) Sang Won Seo, Mee Kyung Suh, Juhee Chin, Duk L. Na * Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 ILwon-dong, Kangnam-ku, Seoul 135-710, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 March 2008 Received in revised form 29 July 2008 Accepted 31 July 2008 Available online 2 October 2008
Mental confusion or delirium can occur after application of scopolamine patch. However, predisposing factors for scopolamine-induced delirium are not known. It is expected that undetected incipient dementia or mild cognitive impairment (MCI) may be prone to develop mental confusion after applying the scopolamine patch. For the past 5 years, we found seven elderly women who had experienced transdermal scopolamine-induced mental confusion. They underwent neuropsychological tests after recovery from mental confusion (mean duration from onset to the test: 66 days). The results showed that all the patients were impaired in at least one of cognitive domains, fulfilling the criteria of MCI. These findings suggest that scopolamine patch-induced mental confusion should be included in the differential diagnoses of mental confusion in elderly, especially in travel situation, and that older people with undetected MCI are prone to develop scopolamine patch-induced mental confusion. ß 2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Transdermal scopolamine patch Delirium Mild cognitive impairment Mental confusion
1. Introduction Scopolamine, a competitive inhibitor of muscarinic acetylcholine, is often used for the prophylaxis and treatment of motion sickness (Rozzini et al., 1988). Acetylcholine is an important neurotransmitter in the brain for mediating cognitive functions such as sustained attention, vigilance, and memory storage (Rozzini et al., 1988). Transdermal scopolamine patch has occasionally been reported to induce mental confusion or cognitive dysfunctions in the elderly (Osterholm and Camoriano, 1982; Rodysill and Warren, 1983; Sennhauser and Schwarz, 1986; Wilkinson, 1987; Mego et al., 1988; Rozzini et al., 1988; Ziskind, 1988; Minagar et al., 1999). However, there had been no detailed descriptions on the onset and duration of mental confusion after administration of the patch, the dosage of scopolamine used, and the types of neurological side effects. In addition, it is unknown whether there are any predisposing factors involved in mental confusion associated with the scopolamine patch. We examined seven patients with mental confusion associated with intradermal scopolamine. In these patients, we provide detailed description of onset, duration, dose of scopolamine, and patterns of mental or behavioral abnormalities. We also hypothesized that elderly people with undetected incipient dementia or
* Corresponding author. Tel.: +82 2 3410 3591/3599; fax: +82 2 3410 0052. E-mail address: [email protected] (D.L. Na). 0167-4943/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2008.07.011
MCI may be prone to develop mental confusion after applying the scopolamine patch. Thus, we reviewed the neuropsychological tests performed in these patients when they had recovered from mental confusion. 2. Subjects and methods 2.1. Patients We found seven patients who visited our Memory Disorder between 2001 and 2006 because of transient mental confusion or behavioral abnormalities probably associated with application of transdermal scopolamine patch. In all patients, the behavioral abnormalities had occurred during a trip after the patch but no patients or their caregivers were aware that the episode was related to the patch. The mean age was 72.4 (range, 65–82) years and their mean education was 6.0 (range, 0–12) years. Their symptoms developed during or immediately after traveling on a plane (n = 4), express bus (n = 2) or a ship (n = 1). Detailed history excluded other possible causes of delirium such as head trauma, infection, and drug use other than the use of scopolamine patch. None of the patients had been to the memory clinic before for cognitive impairment. Laboratory tests including CBC, chemistry, vitamin B12/folate, syphilis serology and thyroid function tests also did not show any cause to explain the patients’ symptoms. Brain MRI scans showed no structural lesions such as territorial cerebral infarction or brain tumor.
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
205
3.2. Neuropsychological findings after recovery from mental confusion
2.2. Neuropsychological tests Along with a clinical interview and a neurological examination, as part of the standard evaluation at our memory clinic, all the patients underwent a standardized battery of neuropsychological tests called the Seoul Neuropsychological Screening Battery (SNSB) (Kang and Na, 2003). The battery contains tests for attention, language, praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual memory, and frontal/ executive function. Among these, the scorable tests comprised the digit span (forward and backward), the Korean version of the Boston Naming Test (K-BNT; Kim and Na, 1999), the Rey-Osterrieth Complex Figure Test (RCFT; copying, immediate and 20-min delayed recall, and recognition), Seoul Verbal Learning Test (SVLT; three learning-free recall trials of 12 words, 20-min delayed recall trial for these 12 items, and a recognition test), semantic Controlled Oral Word Association Test (COWAT), and Stroop Test (color reading of 112 items during a 2-min period). Age-, sex-, and education-specific norms for each test based on 447 normal subjects are available. The scores of these scorable cognitive tests were classified as abnormal when they were below the 16th percentiles of the norms for the age-, sex-, and education-matched normal subjects. By the time the neuropsychological tests were performed, the family members that accompanied the patients told us that the patient had completely recovered from her mental confusion, but they were just visiting our memory disorder clinic because they were afraid that the patient might be demented in the future. The average time interval from mental confusion to the test was 66.6 (range, 3–150) days.
The neuropsychological tests revealed that all the patients were impaired in at least one of the five cognitive domains: attention, confrontational naming, visuospatial function, memory, and frontal executive function (Table 2). Three of the seven patients (Patient 1, 3 and 4) did not complain of any memory disturbances premorbidly despite their cognitive impairments in the neuropsychological tests. In the remaining four, their family noticed before the episode that the patients’ memory function had decreased. Activities of daily living (ADL) were also intact as assessed by clinical interview and Lawton’s-IADL scale. 3.3. Evaluation of our findings Our patients did not have other possible causes of delirium. Although two patients had a past history of liver cirrhosis, there were no signs of recent aggravation and the liver function tests were normal. One possible cause that can be associated with triprelated mental confusion is the alteration in the circadian rhythm (i.e., jet lag). However, most of our patients traveled places within the same time zone except for Patient 1 and 2. Rather, all the patients showed mental confusion during or after the trip with the temporal relationship to the scopolamine patch. In most patients, symptoms disappeared within several hours after the removal of the patch. However, in one patient symptoms persisted for 2 days even after the removal of the patches, which might have been due to continued release of medication from the skin area. Predisposing factors for mental confusion associated with scopolamine patch are unknown. Neuropsychological tests performed several weeks postonset (except Patient 3) showed that all the patients were impaired in at least one of cognitive domains, suggesting that they might have had incipient dementia or MCI premorbidly (Winblad et al., 2004). Acetylcholine is one of the major neurotransmitters that are deficient in the elderly when they progress from normal cognition to Alzheimer’s disease (AD). Recent pathologic studies also showed that MCI lies on this continuum (Mesulam et al., 2004). These findings thus support our observation that the elderly people with MCI are more likely to develop scopolamine-induced mental confusion. Our results may also be in line with a previous report that patients with subclinical dementia are at greater risk of postoperative delirium (Litaker et al., 2001). Recent data demonstrate that people differ in their capacity to withstand AD pathology; e.g., some people, despite extensive AD pathology, do not exhibit cognitive impairment (Bennett et al., 2003). One explanation for this variability is cognitive reserve theory. For instance, AD pathology is more likely to be expressed clinically as dementia in women than in men, and in lower education group than in higher education group (Bennett et al.,
3. Results and discussion 3.1. Clinical features in the acute stage Abnormal behaviors appeared at average 11.7 (3–27) hours after the application of the patch. The mean dosage of scopolamine was 2.25 mg: one patch (1.5 mg) was used in 3/7 while two patches (3.0 mg) were used in 3/7 patients (Patient 4 was excluded from this analysis since her caregiver could not remember the number of patches). Their abnormal behaviors or neurologic symptoms consisted of insomnia (n = 6), restlessness (n = 5), disorientation (n = 4), visual hallucination (n = 2), repetitive behavior (n = 1), gait disturbance (n = 2), dysarthria (n = 1), delusion (n = 1), dizziness (n = 1), and headache (n = 1). Their symptoms persisted for average 2.0 days (range, 1–4 days) and disappeared within several hours after the removal of the patch. However, in one patient who used 3.0 mg, the symptoms had persisted for 2 days even after the removal of the patch. Demographic data and characteristics of abnormal behaviors are presented in Table 1.
Table 1 Clinical characteristics of our patients in the ictal phase Patient
Age/sex
Past history
Dose (mg)/no.
Hours of application
Onset hours after application
Type of trip
Duration of symptoms
Main symptoms
1
82/F
HT
3.0/2
26
15
Flight
2 days
2
71/F
COI
3.0/2
20
5
Flight
1 day
3 4 5 6 7
71/F 70/F 65/F 76/F 72/F
LC MI LC HT HT
NA 1.5/1 1.5/1 1.5/1 3.0/2
NA NA 48 96 7
15 3 7 10 27
Bus Ship Bus Flight Flight
2 1 2 4 2
Hallucination, disorientation in person and place, restlessness, repetitive behavior, eating change, abulia, insomnia Restlessness, inappropriateness, disorientation in person and place, insomnia Hallucination, dizziness, logorrhea, headache, insomnia Restlessness, dysarthria, ataxia, insomnia Postural instability, festinating gait, logorrhea, restlessness, insomnia Disorientation in place, delusion Disorientation in person, insomnia, restlessness
days day days days days
Notes: no. = number, HT = hypertension, COI = carbon-monoxide intoxication, LC = liver cirrhosis, MI = myocardial infarction, NA = not applicable.
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
206
Table 2 Results of the neuropsychological tests after recovery from mental confusion Tested function
Time from onset (days) 150a
95b
3c
26d
27e
129f
36g
Attention Digit-span (For) Digit-span (Back)
3h/3 3h/3
5h/3 5h/3
4/2 4/2
5/3 5/3
3h/2h 3h/2h
6/2 6/2
5h/3h 5h/3h
Language and related functions BNT (60) Praxis (5) Calculation (12)
26h 5 12
31h 5 12
32 5 6
34 5 6
40 5 12
38 5 3
38h 5 6
Visuospatial functions Copy of RCFT (36)
32
35
22
31
32.5
2h
26.5h
Memory functions SVLT-IR (12 + 12 + 12) SVLT-DR (12) Recognition (TP-FP) RCFT-IR (36) RCFT-DR (36) Recognition (TP-FP)
1 + 3 + 4h 1h 9 1=8 10 11.5 10 3 = 7
4 + 5 + 7h 4h 10 2 = 8 4h 7h 10 4 = 6h
2+5+8 3 12 1 = 11 0.5h 2h 7 0=7
2+5+7 2h 8 2=6 4 4 11 3 = 8
4+7+8 6 10 2 = 8 14 14 9 2=7
1 + 3 + 3* 1h 6 2 = 4h 2 2h 10 5 = 5
4+5+7 4h 9 0=9 3h 5h 11 5 = 6h
Frontal functions COWAT-A COWAT-S Stroop test_C (112) MMSE (30) CDR Barthel index (20) IADL
9h 19 59 29 0 20 1/11
13 16 89 29 0.5 20 1/10
9h 12 22h 22 0 20 1/11
11 13 80 26 0 20 1/11
12 13 79h 26 0.5 20 0/11
8h 10 43 25 0.5 20 3/11
8h 19 80 28 0.5 20 0/11
a
Patient 1 (education (years) = 6). Patient 2 (education (years) = 12). c Patient 3 (education (years) = 0). d Patient 4 (education (years) = 0). e Patient 5 (education (years) = 12). f Patient 6 (education (years) = 12). g Patient 7 (education (years) = 0). h <16% tile, SVLT: Seoul verbal learning test, K-BNT: the Korean version of Boston Naming Test, DR: delayed recall, IR: immediate recall, TP: true positive, FP: false positive, RCFT: Rey-Osterrieth Complex Figure Test, COWAT: Controlled Oral Word Association Test, CDR: Clinical Dementia Rating. b
2003; Barnes et al., 2005). Most (4/7) of our patients had education of 6 years or less and all the patients were female. Thus, gender and low education effects along with an MCI state might have contributed to the occurrence of scopolamine-induced abnormal
behaviors. The fact that most of the people who were previously reported to have transdermal scopolamine patch-induced psychosis were female and elderly support our hypothesis (Table 3) (Osterholm and Camoriano, 1982; Rodysill and Warren, 1983;
Table 3 Clinical characteristics of previously reported cases Source
Age/sex
Past history
Patch no.
Hours of application
Onset hours after application
Type of trip
Duration after rem.
Main symptoms
Osterholm and Camoriano (1982) Rodysill and Warren (1983) Sennhauser and Schwarz (1986)
71/F
NA
1
NA
NA
NA
3h
76/F
1
8
NA
NA
24 h
6/F
Herpes zoster oticus NA
1
12
NA
NA
14 h
Hallucination, agitation, paranoid behavior, dilated pupil, tachycardia, dizziness Confusion, agitation, rambling, hallucination, delusion, dizziness Confusion, confabulation, temporal and spatial disorientation, unsteady gait, dry mouth, dilated pupil
Wilkinson (1987) Case 1 Case 2
12/M 15/F
None None
1 1
14 14
NA NA
Flight, car Flight, car
2 days 2 days
Hallucination, confusion, dilated pupil Hallucination, confusion, dilated pupil
Mego et al. (1988) Case 1
82/M
NA
1
NA
NA
NA
24 h
84/F
HT, PAD
NA
NA
NA
NA
NA
Hallucination, agitation, restlessness, tremulous, ataxic, memory impairment, dry skin, dry mouth, dizziness Hallucination, dizziness skin, dry mouth, dilated pupil
Rozzini et al. (1988)
77/F
NA
1
NA
NA
Car
NA
Ziskind (1988)
60/F
1
NA
NA
Cruise
36 h
Minagar et al. (1999)
64/F
HT, allergic rhinitis PD
1
Within 24 h
10–12 h
Cruise
2 days
Case 2
Notes: PAD: peripheral arterial disease, PD: Parkinson’s disease, no.: number, HTN: hypertension, NA: not applicable.
Memory impairment, disorientation, clouded sensorium Hallucination, agitation, dry mouth, blurred vision, drowsiness Hallucination, confusion, agitation, delusion
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
Sennhauser and Schwarz, 1986; Wilkinson, 1987; Mego et al., 1988; Rozzini et al., 1988; Ziskind, 1988; Minagar et al., 1999). Lastly, our patients showed abnormal behaviors associated with trips especially those of flight, but the patients and their caregivers did not know that the behaviors can be related to the patch. Thus, in the elderly who show abnormal behaviors or mental confusion during or immediately after flight, the possibility of scopolamine-induced confusion should be considered. The current study may have several limitations. First, there was no control group. Thus, we cannot completely exclude the possibility that delirium of our patients might have been caused by trip-related stress. Second, some patients visited our clinic several months after confusion. Thus, the history of some patients, especially the onset and duration of delirium, may not be as accurate as it should be. Conflict of interest statement None. Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079). References Barnes, L.L., Wilson, R.S., Bienias, J.L., Schneider, J.A., Evans, D.A., Bennett, D.A., 2005. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685–691.
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Bennett, D.A., Wilson, R.S., Schneider, J.A., Evans, D.A., Mendes de Leon, C.F., Arnold, S.E., Barnes, L.L., Bienias, J.L., 2003. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology 60, 1909–1915. Kang, Y., Na, D.L., 2003. Seoul Neuropsychological Screening Battery. Human Brain Research and Consulting Co., Incheon. Kim, H., Na, D.L., 1999. Normative data on the Korean version of the Boston Naming Test. J. Clin. Exp. Neuropsychol. 21, 127–133. Litaker, D., Locala, J., Franco, K., Bronson, D.L., Tannous, Z., 2001. Preoperative risk factors for postoperative delirium. Gen. Hosp. Psychiatry 23, 84–89. Mego, D.M., Omori, J.M., Hanley, J.F., 1988. Transdermal scopolamine as a cause of transient psychosis in two elderly patients. South. Med. J. 81, 394–395. Mesulam, M., Shaw, P., Mash, D., Weintraub, S., 2004. Cholinergic nucleus basalis tauopathy emerges early in the aging-MCI-AD continuum. Ann. Neurol. 55, 815–828. Minagar, A., Shulman, L.M., Weiner, W.J., 1999. Transderm-induced psychosis in Parkinson’s disease. Neurology 53, 433–434. Osterholm, R.K., Camoriano, J.K., 1982. Transdermal scopolamine psychosis. J. Am. Med. Assoc. 247, 3081. Rodysill, K.J., Warren, J.B., 1983. Transdermal scopolamine and toxic psychosis. Ann. Intern. Med. 98, 561. Rozzini, R., Inzoli, M., Trabucchi, M., 1988. Delirium from transdermal scopolamine in an elderly woman. J. Am. Med. Assoc. 260, 478. Sennhauser, F.H., Schwarz, H.P., 1986. Toxic psychosis from transdermal scopolamine in a child. Lancet 2, 1033. Wilkinson, J.A., 1987. Side effects of transdermal scopolamine. J. Emerg. Med. 5, 389–392. Winblad, B., Palmer, K., Kivipelto, M., Jelic, V., Fratiglioni, L., Wahlund, L.O., Nordberg, A., Backman, L., Albert, M., Almkvist, O., Arai, H., Basun, H., Blennow, K., De Leon, M., DeCarli, C., Erkinjuntti, T., Giacobini, E., Graff, C., Hardy, J., Jack, C., Jorm, A., Ritchie, K., Van Duijn, C., Visser, P., Petersen, R.C., 2004. Mild cognitive impairment - beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med. 256, 240–246. Ziskind, A.A., 1988. Transdermal scopolamine-induced psychosis. Postgrad. Med. 84, 73–76.
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Archives of Gerontology and Geriatrics journal homepage: www.elsevier.com/locate/archger
Mental confusion associated with scopolamine patch in elderly with mild cognitive impairment (MCI) Sang Won Seo, Mee Kyung Suh, Juhee Chin, Duk L. Na * Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 ILwon-dong, Kangnam-ku, Seoul 135-710, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 March 2008 Received in revised form 29 July 2008 Accepted 31 July 2008 Available online 2 October 2008
Mental confusion or delirium can occur after application of scopolamine patch. However, predisposing factors for scopolamine-induced delirium are not known. It is expected that undetected incipient dementia or mild cognitive impairment (MCI) may be prone to develop mental confusion after applying the scopolamine patch. For the past 5 years, we found seven elderly women who had experienced transdermal scopolamine-induced mental confusion. They underwent neuropsychological tests after recovery from mental confusion (mean duration from onset to the test: 66 days). The results showed that all the patients were impaired in at least one of cognitive domains, fulfilling the criteria of MCI. These findings suggest that scopolamine patch-induced mental confusion should be included in the differential diagnoses of mental confusion in elderly, especially in travel situation, and that older people with undetected MCI are prone to develop scopolamine patch-induced mental confusion. ß 2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Transdermal scopolamine patch Delirium Mild cognitive impairment Mental confusion
1. Introduction Scopolamine, a competitive inhibitor of muscarinic acetylcholine, is often used for the prophylaxis and treatment of motion sickness (Rozzini et al., 1988). Acetylcholine is an important neurotransmitter in the brain for mediating cognitive functions such as sustained attention, vigilance, and memory storage (Rozzini et al., 1988). Transdermal scopolamine patch has occasionally been reported to induce mental confusion or cognitive dysfunctions in the elderly (Osterholm and Camoriano, 1982; Rodysill and Warren, 1983; Sennhauser and Schwarz, 1986; Wilkinson, 1987; Mego et al., 1988; Rozzini et al., 1988; Ziskind, 1988; Minagar et al., 1999). However, there had been no detailed descriptions on the onset and duration of mental confusion after administration of the patch, the dosage of scopolamine used, and the types of neurological side effects. In addition, it is unknown whether there are any predisposing factors involved in mental confusion associated with the scopolamine patch. We examined seven patients with mental confusion associated with intradermal scopolamine. In these patients, we provide detailed description of onset, duration, dose of scopolamine, and patterns of mental or behavioral abnormalities. We also hypothesized that elderly people with undetected incipient dementia or
* Corresponding author. Tel.: +82 2 3410 3591/3599; fax: +82 2 3410 0052. E-mail address: [email protected] (D.L. Na). 0167-4943/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2008.07.011
MCI may be prone to develop mental confusion after applying the scopolamine patch. Thus, we reviewed the neuropsychological tests performed in these patients when they had recovered from mental confusion. 2. Subjects and methods 2.1. Patients We found seven patients who visited our Memory Disorder between 2001 and 2006 because of transient mental confusion or behavioral abnormalities probably associated with application of transdermal scopolamine patch. In all patients, the behavioral abnormalities had occurred during a trip after the patch but no patients or their caregivers were aware that the episode was related to the patch. The mean age was 72.4 (range, 65–82) years and their mean education was 6.0 (range, 0–12) years. Their symptoms developed during or immediately after traveling on a plane (n = 4), express bus (n = 2) or a ship (n = 1). Detailed history excluded other possible causes of delirium such as head trauma, infection, and drug use other than the use of scopolamine patch. None of the patients had been to the memory clinic before for cognitive impairment. Laboratory tests including CBC, chemistry, vitamin B12/folate, syphilis serology and thyroid function tests also did not show any cause to explain the patients’ symptoms. Brain MRI scans showed no structural lesions such as territorial cerebral infarction or brain tumor.
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
205
3.2. Neuropsychological findings after recovery from mental confusion
2.2. Neuropsychological tests Along with a clinical interview and a neurological examination, as part of the standard evaluation at our memory clinic, all the patients underwent a standardized battery of neuropsychological tests called the Seoul Neuropsychological Screening Battery (SNSB) (Kang and Na, 2003). The battery contains tests for attention, language, praxis, four elements of Gerstmann syndrome, visuoconstructive function, verbal and visual memory, and frontal/ executive function. Among these, the scorable tests comprised the digit span (forward and backward), the Korean version of the Boston Naming Test (K-BNT; Kim and Na, 1999), the Rey-Osterrieth Complex Figure Test (RCFT; copying, immediate and 20-min delayed recall, and recognition), Seoul Verbal Learning Test (SVLT; three learning-free recall trials of 12 words, 20-min delayed recall trial for these 12 items, and a recognition test), semantic Controlled Oral Word Association Test (COWAT), and Stroop Test (color reading of 112 items during a 2-min period). Age-, sex-, and education-specific norms for each test based on 447 normal subjects are available. The scores of these scorable cognitive tests were classified as abnormal when they were below the 16th percentiles of the norms for the age-, sex-, and education-matched normal subjects. By the time the neuropsychological tests were performed, the family members that accompanied the patients told us that the patient had completely recovered from her mental confusion, but they were just visiting our memory disorder clinic because they were afraid that the patient might be demented in the future. The average time interval from mental confusion to the test was 66.6 (range, 3–150) days.
The neuropsychological tests revealed that all the patients were impaired in at least one of the five cognitive domains: attention, confrontational naming, visuospatial function, memory, and frontal executive function (Table 2). Three of the seven patients (Patient 1, 3 and 4) did not complain of any memory disturbances premorbidly despite their cognitive impairments in the neuropsychological tests. In the remaining four, their family noticed before the episode that the patients’ memory function had decreased. Activities of daily living (ADL) were also intact as assessed by clinical interview and Lawton’s-IADL scale. 3.3. Evaluation of our findings Our patients did not have other possible causes of delirium. Although two patients had a past history of liver cirrhosis, there were no signs of recent aggravation and the liver function tests were normal. One possible cause that can be associated with triprelated mental confusion is the alteration in the circadian rhythm (i.e., jet lag). However, most of our patients traveled places within the same time zone except for Patient 1 and 2. Rather, all the patients showed mental confusion during or after the trip with the temporal relationship to the scopolamine patch. In most patients, symptoms disappeared within several hours after the removal of the patch. However, in one patient symptoms persisted for 2 days even after the removal of the patches, which might have been due to continued release of medication from the skin area. Predisposing factors for mental confusion associated with scopolamine patch are unknown. Neuropsychological tests performed several weeks postonset (except Patient 3) showed that all the patients were impaired in at least one of cognitive domains, suggesting that they might have had incipient dementia or MCI premorbidly (Winblad et al., 2004). Acetylcholine is one of the major neurotransmitters that are deficient in the elderly when they progress from normal cognition to Alzheimer’s disease (AD). Recent pathologic studies also showed that MCI lies on this continuum (Mesulam et al., 2004). These findings thus support our observation that the elderly people with MCI are more likely to develop scopolamine-induced mental confusion. Our results may also be in line with a previous report that patients with subclinical dementia are at greater risk of postoperative delirium (Litaker et al., 2001). Recent data demonstrate that people differ in their capacity to withstand AD pathology; e.g., some people, despite extensive AD pathology, do not exhibit cognitive impairment (Bennett et al., 2003). One explanation for this variability is cognitive reserve theory. For instance, AD pathology is more likely to be expressed clinically as dementia in women than in men, and in lower education group than in higher education group (Bennett et al.,
3. Results and discussion 3.1. Clinical features in the acute stage Abnormal behaviors appeared at average 11.7 (3–27) hours after the application of the patch. The mean dosage of scopolamine was 2.25 mg: one patch (1.5 mg) was used in 3/7 while two patches (3.0 mg) were used in 3/7 patients (Patient 4 was excluded from this analysis since her caregiver could not remember the number of patches). Their abnormal behaviors or neurologic symptoms consisted of insomnia (n = 6), restlessness (n = 5), disorientation (n = 4), visual hallucination (n = 2), repetitive behavior (n = 1), gait disturbance (n = 2), dysarthria (n = 1), delusion (n = 1), dizziness (n = 1), and headache (n = 1). Their symptoms persisted for average 2.0 days (range, 1–4 days) and disappeared within several hours after the removal of the patch. However, in one patient who used 3.0 mg, the symptoms had persisted for 2 days even after the removal of the patch. Demographic data and characteristics of abnormal behaviors are presented in Table 1.
Table 1 Clinical characteristics of our patients in the ictal phase Patient
Age/sex
Past history
Dose (mg)/no.
Hours of application
Onset hours after application
Type of trip
Duration of symptoms
Main symptoms
1
82/F
HT
3.0/2
26
15
Flight
2 days
2
71/F
COI
3.0/2
20
5
Flight
1 day
3 4 5 6 7
71/F 70/F 65/F 76/F 72/F
LC MI LC HT HT
NA 1.5/1 1.5/1 1.5/1 3.0/2
NA NA 48 96 7
15 3 7 10 27
Bus Ship Bus Flight Flight
2 1 2 4 2
Hallucination, disorientation in person and place, restlessness, repetitive behavior, eating change, abulia, insomnia Restlessness, inappropriateness, disorientation in person and place, insomnia Hallucination, dizziness, logorrhea, headache, insomnia Restlessness, dysarthria, ataxia, insomnia Postural instability, festinating gait, logorrhea, restlessness, insomnia Disorientation in place, delusion Disorientation in person, insomnia, restlessness
days day days days days
Notes: no. = number, HT = hypertension, COI = carbon-monoxide intoxication, LC = liver cirrhosis, MI = myocardial infarction, NA = not applicable.
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
206
Table 2 Results of the neuropsychological tests after recovery from mental confusion Tested function
Time from onset (days) 150a
95b
3c
26d
27e
129f
36g
Attention Digit-span (For) Digit-span (Back)
3h/3 3h/3
5h/3 5h/3
4/2 4/2
5/3 5/3
3h/2h 3h/2h
6/2 6/2
5h/3h 5h/3h
Language and related functions BNT (60) Praxis (5) Calculation (12)
26h 5 12
31h 5 12
32 5 6
34 5 6
40 5 12
38 5 3
38h 5 6
Visuospatial functions Copy of RCFT (36)
32
35
22
31
32.5
2h
26.5h
Memory functions SVLT-IR (12 + 12 + 12) SVLT-DR (12) Recognition (TP-FP) RCFT-IR (36) RCFT-DR (36) Recognition (TP-FP)
1 + 3 + 4h 1h 9 1=8 10 11.5 10 3 = 7
4 + 5 + 7h 4h 10 2 = 8 4h 7h 10 4 = 6h
2+5+8 3 12 1 = 11 0.5h 2h 7 0=7
2+5+7 2h 8 2=6 4 4 11 3 = 8
4+7+8 6 10 2 = 8 14 14 9 2=7
1 + 3 + 3* 1h 6 2 = 4h 2 2h 10 5 = 5
4+5+7 4h 9 0=9 3h 5h 11 5 = 6h
Frontal functions COWAT-A COWAT-S Stroop test_C (112) MMSE (30) CDR Barthel index (20) IADL
9h 19 59 29 0 20 1/11
13 16 89 29 0.5 20 1/10
9h 12 22h 22 0 20 1/11
11 13 80 26 0 20 1/11
12 13 79h 26 0.5 20 0/11
8h 10 43 25 0.5 20 3/11
8h 19 80 28 0.5 20 0/11
a
Patient 1 (education (years) = 6). Patient 2 (education (years) = 12). c Patient 3 (education (years) = 0). d Patient 4 (education (years) = 0). e Patient 5 (education (years) = 12). f Patient 6 (education (years) = 12). g Patient 7 (education (years) = 0). h <16% tile, SVLT: Seoul verbal learning test, K-BNT: the Korean version of Boston Naming Test, DR: delayed recall, IR: immediate recall, TP: true positive, FP: false positive, RCFT: Rey-Osterrieth Complex Figure Test, COWAT: Controlled Oral Word Association Test, CDR: Clinical Dementia Rating. b
2003; Barnes et al., 2005). Most (4/7) of our patients had education of 6 years or less and all the patients were female. Thus, gender and low education effects along with an MCI state might have contributed to the occurrence of scopolamine-induced abnormal
behaviors. The fact that most of the people who were previously reported to have transdermal scopolamine patch-induced psychosis were female and elderly support our hypothesis (Table 3) (Osterholm and Camoriano, 1982; Rodysill and Warren, 1983;
Table 3 Clinical characteristics of previously reported cases Source
Age/sex
Past history
Patch no.
Hours of application
Onset hours after application
Type of trip
Duration after rem.
Main symptoms
Osterholm and Camoriano (1982) Rodysill and Warren (1983) Sennhauser and Schwarz (1986)
71/F
NA
1
NA
NA
NA
3h
76/F
1
8
NA
NA
24 h
6/F
Herpes zoster oticus NA
1
12
NA
NA
14 h
Hallucination, agitation, paranoid behavior, dilated pupil, tachycardia, dizziness Confusion, agitation, rambling, hallucination, delusion, dizziness Confusion, confabulation, temporal and spatial disorientation, unsteady gait, dry mouth, dilated pupil
Wilkinson (1987) Case 1 Case 2
12/M 15/F
None None
1 1
14 14
NA NA
Flight, car Flight, car
2 days 2 days
Hallucination, confusion, dilated pupil Hallucination, confusion, dilated pupil
Mego et al. (1988) Case 1
82/M
NA
1
NA
NA
NA
24 h
84/F
HT, PAD
NA
NA
NA
NA
NA
Hallucination, agitation, restlessness, tremulous, ataxic, memory impairment, dry skin, dry mouth, dizziness Hallucination, dizziness skin, dry mouth, dilated pupil
Rozzini et al. (1988)
77/F
NA
1
NA
NA
Car
NA
Ziskind (1988)
60/F
1
NA
NA
Cruise
36 h
Minagar et al. (1999)
64/F
HT, allergic rhinitis PD
1
Within 24 h
10–12 h
Cruise
2 days
Case 2
Notes: PAD: peripheral arterial disease, PD: Parkinson’s disease, no.: number, HTN: hypertension, NA: not applicable.
Memory impairment, disorientation, clouded sensorium Hallucination, agitation, dry mouth, blurred vision, drowsiness Hallucination, confusion, agitation, delusion
S.W. Seo et al. / Archives of Gerontology and Geriatrics 49 (2009) 204–207
Sennhauser and Schwarz, 1986; Wilkinson, 1987; Mego et al., 1988; Rozzini et al., 1988; Ziskind, 1988; Minagar et al., 1999). Lastly, our patients showed abnormal behaviors associated with trips especially those of flight, but the patients and their caregivers did not know that the behaviors can be related to the patch. Thus, in the elderly who show abnormal behaviors or mental confusion during or immediately after flight, the possibility of scopolamine-induced confusion should be considered. The current study may have several limitations. First, there was no control group. Thus, we cannot completely exclude the possibility that delirium of our patients might have been caused by trip-related stress. Second, some patients visited our clinic several months after confusion. Thus, the history of some patients, especially the onset and duration of delirium, may not be as accurate as it should be. Conflict of interest statement None. Acknowledgement This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (A050079). References Barnes, L.L., Wilson, R.S., Bienias, J.L., Schneider, J.A., Evans, D.A., Bennett, D.A., 2005. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685–691.
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