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Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis
Journal of the Neurological Sciences 245 (2006) 177 – 181 www.elsevier.com/locate/jns
Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis J. Porcel *, X. Montalban 2a Planta EUI, Unitat de Neuroimmunologia Clı´nica, Hospital Universitari Vall d’Hebron, Ps. Vall d’Hebron 119-129, 08035, Barcelona, Spain Received 4 April 2005; received in revised form 27 June 2005; accepted 8 July 2005 Available online 3 May 2006
Abstract Neuropsychological impairment is a common manifestation in multiple sclerosis (MS) and is found in 40 – 60% of patients. The pattern of cognitive impairment in MS is characterized by difficulties in recent memory, sustained attention, executive functions and information processing speed. These cognitive deficits have a significant impact on the patients’ daily activities. However, there is no specific treatment available at present for cognitive disorders in MS patients. Treatment with acetylcholinesterase inhibitors (AChEI) has shown a positive effect on cognitive functions of patients with Alzheimer’s disease and other conditions such as Lewy Body dementia, subcortical vascular dementia and Parkinson’s disease. In this paper we review the results from studies and clinical trials aiming to demonstrate that AChEI could be a potential treatment for cognitive disorders in MS patients. Finally, we discuss future issues to take into consideration for AChEI treatments in the context of MS. D 2006 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Anticholinesterasics; Cognitive impairment; Rivastigmine; Donezepil
1. Introduction Neuropsychological studies have extensively described the presence of cognitive dysfunction in multiple sclerosis (MS) patients [1] that may result from the disruption of cortical and subcortical pathways as a consequence of demyelination and axonal transection. About half of the diagnosed patients will experience problems with their memory, concentration, attention and other cognitive capacities in the course of the illness [2,3]. Cognitive impairment, ranging from mild deficit to dementia, clearly impacts on the patient’s life. Rates of unemployment are high among patients with cognitive impairment, social isolation is greater and the need for more home
* Corresponding author. Tel.: +34 932746202; fax: +34 932746084. E-mail address: [email protected] (J. Porcel). 0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.07.021
assistance clearer than for patients without cognitive disorders [4]. Much of this deficit causes trouble to the patients and their families. No specific treatment is yet available for cognitive disorders in MS. One possible treatment could be based on the use of acetylcholinesterase inhibitors (AChEI), which have shown efficacy not only in Alzheimer’s disease [5] but also in other cognitive disorders such as dementia with Lewy bodies [6], Parkinson’s disease [7], vascular dementia [8] and traumatic brain injury [9]. AChEI may therefore represent a potential therapeutic option for impaired cognitive status in MS because the cholinergic system is probably affected in the course of the disease and can underlie the cognitive deficits seen in those patients. Further reasons to favor AChEI in the treatment of MS patients lie in the hypothesis that several structures associated with the cholinergic system, such as the temporal lobe, the hippocampus and the thalamus, could be related to cognitive impairment in MS, especially memory [10,11].
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J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181
2. AchEI to treat cognitive impairment in MS: pilot studies Early pilot studies, conducted on small populations of MS patients, have shown that physostigmine and lecithin can improve memory, but their side effects have limited their use [12,13]. The effect of AChEI has also been very recently evidenced in MS, using fMRI [14]. In this study, brain activation patterns have been shown to be different between MS patients and controls before treatment, but tend to normalize after administration of rivastigmine. The authors concluded that functional plasticity was an acute response to AChEI.
3. Donepezil to treat cognitive impairments in MS: clinical trials Several studies have addressed the effect of donepezil on cognitive dysfunction in MS patients (Table 1). In 2000, Greene et al. [15] reported the results of an open trial with donepezil administered over 12 weeks to 17 moderate-to-severe cognitively impaired patients (Mini Mental Status Examination (MMSE) equal or below 25 points). Patients were evaluated by means of a comprehensive neuropsychological battery including measures of impression of change, behavioral symptoms and activities of daily living (Table 2). Efficacy parameters were obtained at baseline, and after 4 and 12 weeks. The authors observed an improvement in several cognitive domains and behavioral aspects. The positive effect of the drug on cognition was coupled by good tolerability; only one case of spasticity was related to the administration of donepezil. Although preliminary and with obvious methodological limitations, these results emphasized the importance of conducting large clinical trials to test the possible role of AChEI in the treatment of MS cognitive disorders. Rorie et al. [16] designed a randomized, double blind, placebo-controlled, crossover trial. Inclusion criteria of MS patients were based on memory complaints and objective cognitive dysfunction assessed by the examiner. Assessment, including several neuropsychological tasks (Table 2), was performed at baseline and after 6 weeks of treatment with donepezil. After a 2-week washout period, patients
were then crossed over to placebo or donepezil and retested after another 6 weeks of treatment. Thirty-two patients were enrolled in this trial and 25 completed the whole study protocol. The authors failed to find a treatment effect on cognition and concluded that donepezil may not be useful to treat cognitive problems in MS. No indication about adverse effects could be derived from this report [16]. In the study of Bosca` et al. [17], 27 patients with secondary progressive MS were enrolled in a 6-month, randomized, double blind, placebo-controlled trial and assessed with a comprehensive neuropsychological battery (Table 2) at baseline and 6 months after treatment initiation. Cognitive status of patients was not reported. Seven patients (4 in the placebo group and 3 in the treatment arm) withdrew from the study due to side effects. The authors concluded that the drug was well tolerated, but due to the small sample size it was difficult to establish the efficacy of the treatment. In fact only a slight improvement in semantic language fluency was observed. Decoo et al. [18] conducted a 6-month, randomized, double blind, placebo-controlled, crossover trial. Fifty MS patients with mild to moderate cognitive deficit, defined as a score below two standard deviations in the PASAT performance and a score equal to or above 27 points in the MMSE were included. Neuropsychological assessment (Table 2) was performed at baseline, 3 and 6 months after treatment initiation. Only four patients gave up the trial due to adverse effects (3 in the treatment group because of gastrointestinal problems and 1 patient in the placebo group because of headache). Efficacy measures showed better scores during the donepezil period in the psychosocial dimension of the Sickness Impact Profile, and in different measures of executive function (Stroop test, verbal fluency and Wisconsin Card Sorting Test). Krupp et al. [19] have reported the results of the largest study published to date. It consisted in a 24-week, randomized, double blind, placebo-controlled trial with donepezil to study MS patients who fulfilled the following inclusion criteria: mild memory impairment and no severe cognitive impairment (a score of at least 0.5 standard deviations below normative data adjusted for age and sex in a memory task (Rey Auditory Verbal Learning Test) with a score equal to or above 26 in the MMSE), and no severe depression symptoms (scores in the Montgomery Ashberg Depression Scale equal to or below 14 points). Measures
Table 1 Summary of the studies described
Greene et al., 2000 Rorie et al., 2001 Bosca` et al., 2004 Decoo et al., 2004 Krupp et al., 2004
Patients cognitive status
Anticholinesterasics Tolerability
Cognitive effect
n = 17, n = 32, n = 27, n = 50, n = 69,
Well tolerated Not indicated Well tolerated Well tolerated Well tolerated
Positive effect No effect Positive effect Positive effect Positive effect
MMSE r 25 Complaints of memory loss Not indicated Mild to moderate At least mild memory deficit
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181 Table 2 Neuropsychological tests included in AChEI studies with MS patients Study (author, year)
Neuropsychological assessment
Greene et al., 2000
Primary outcome measures Mini-Mental Status Examination Hopkins Verbal Learning Test Clinical Global Impression of Change Secondary outcome measures Brief Test of Attention Digit Span Test Boston Naming Test Controlled Oral Word Association Test Motor-Free Visual Perception Test Mattis Dementia Rating Scale Neuropsychiatric Inventory Questionnaire Logical Memory (immediate and delayed) Paired Associate Learning Verbal Fluency Verbal Learning Letter Cancellation Trail Making Test Visual Reaction Time Mini-Mental Status Examination Verbal IQ (WAIS III) Set Test Controlled Oral Word Association Test Weschler Memory Scale Wisconsin Card Sorting Test Trail Making Test Stroop Test Boston Test Benton (Form D) Beck Depression Scale Hamilton Anxiety Scale National Adult Reading Test Word Fluency Auditory Verbal Learning Test Stroop Color Word Test Hooper Visual Organization Test Wisconsin Card Sorting Test Dysexecutive Questionnaire Sickness Impact Profile Primary outcome measure Selective Reminding Test (total recall) Secondary outcome measures 10/36 Spatial Recall Test Symbol Digit Modalities Test Paced Auditory Serial Addition Test Controlled Oral Word Association Tower of Hanoi Simple Visual Reaction Time Symbol Digit Modalities Test Paced Auditory Serial Addition Test Continuous Performance Test Rey Auditory-Verbal Learning Test Rey-Osterrieth Complex Figure Test Digit Subtest (WAIS III) Figural Memory (WMS-R) Trail Making Test Wisconsin Card Sorting Test Stroop Test Set Test Controlled Oral Word Association Test Vocabulary Subtest (WAIS III) Hospital Anxiety and Depression Scale
Rorie et al., 2001
Bosca` et al., 2004
Decoo et al., 2004
Krupp et al., 2004
Porcel et al., 2003
179
Table 2 (continued) Study (author, year)
Neuropsychological assessment
Porcel et al., 2003
SF-36 Neuropsychiatric Inventory Questionnaire Test of Reporter Clinical Global Impression of Change
were obtained at baseline in 69 patients then randomized to donepezil (35 patients) or placebo (34 patients) groups. After 24 weeks of treatment, participants were reassessed. Seven patients (2 because of side effects) in the donepezil arm and 5 patients (3 because of side effects) in the placebo group were lost to follow-up. The primary outcome measure was change in the total recall of the verbal memory task included in the Brief Repeatable Battery of Neuropsychological Tests. The other cognitive tasks of the battery and the Tower of Hanoi test were secondary outcomes, in addition to the clinician’s impression of cognitive change and the patient’s self-impression of memory change (Table 2). The results showed that treated patients verbal memory improved in about 10% from mean baseline. Other secondary measures related to verbal memory improved significantly more in the treated group while the other cognitive variables did not differ between groups. Statistically significant differences were also found in both patients and clinicians impressions of change; more treated patients reported improvement in memory compared with the placebo group (66% vs. 32%) and more clinicians observed cognitive improvement in the donepezil arm when compared with the placebo group (54% vs. 29%). Most common adverse effects were the reporting of abnormal dreaming during sleep (34%), diarrhoea (26%), nausea (26%), spasticity (17%) and numbness (17%). Because groups only statistically differed in the reporting of abnormal dreaming, the authors concluded that the drug was relatively well tolerated. Recently, the authors have reported the results of the MRI study, which included 26 MS patients, performed within the donepezil clinical trial [20]. The report concludes that longitudinal brain atrophy was the only measure that correlated with change in cognitive performance over a 6month period. Interestingly, the authors did not observe differences in the MRI measures between the medication groups. To summarize, current data from the literature indicates that AChEI may be useful to treat cognitive deficit present in MS patients; with good tolerability, despite some otherwise usual side effects.
4. Rivastigmine to treat cognitive impairment in MS: clinical trials We are currently conducting a clinical trial at our MS unit to test the efficacy and safety of rivastigmine, another AChEI, to treat patients with severe cognitive impairment who fulfill the criteria of dementia according to the
180
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181
Diagnostic and Statistical Manual of Mental Disorders-IV or the Clinical Dementia Rating Scale (stage 1 or higher) [21]. The study is a 36-week, randomized, double blind, placebo-controlled trial including a 12-week screening period, a baseline period, a dose-escalation period (from baseline to week 24), a maintenance period (from week 24 to week 36) and a post-treatment period (from week 36 on to week 48). A neuropsychologist blinded as to the patients evolution throughout the study as well as to the presence of adverse effects, assesses patients with a comprehensive neuropsychological battery (Table 2). To control for practice effects, a screening assessment is included together with the use of tasks with alternate forms. Whenever this was not possible, the specific task was limited to the baseline and the end-of-treatment visits. Because the included patients have severe cognitive impairment, participation in the study requires the close collaboration of a caregiver who is willing to take on responsibility for monitoring treatment compliance as well as the patient’s condition throughout the study providing information on the efficacy variables. In this sense, we include the assessment of behavioral aspects using the Neuropsychiatric Inventory Questionnaire and the impression of cognitive change by the caregiver using the Test of Reporter. This is the first study to test rivastigmine, a new AchEI with selectivity for the hippocampus and cortex [5] with previously proven efficacy on cognition in Alzheimer’s disease patients [5]. With the aim to detect a positive drug effect, the study protocol covers all the cognitive areas where impairment could be found in MS patients. The inclusion of caregivers’ reportings will also aid to distinguish between neuropsychological performance and change occurring in real life. Finally, the results of this study will increase knowledge on the effect of AchEI in demented MS patients, which stands approximately at 20% to 30% of the patients with cognitive impairment [22].
5. Discussion and conclusion In the recent past, there has been an increasing interest in testing new therapeutic approaches to cognitive dysfunction in MS. As suggested by the studies reviewed in this paper, AChEI may be a valid candidate. Now, it would be necessary to perform large multicentre trials to confirm these results. Design of new studies should also aim to find answers to other issues related with efficacy and safety at long term as well as withdrawal effects and treatment duration. However, to begin with AChEI research in MS needs to approach two key questions. First, what patients will be treated? And second, what outcome measures will be used? Because MS cognitive disorders comprise a wide spectrum from mild deficit to dementia, we need to define what patients will most benefit from treatment and hence
whether it is more appropriate to treat a patient upon early cognitive complaints or to defer until cognitive impairment significantly impacts in daily living. It is also necessary to identify useful outcome measures. Results from the studies reviewed above and from other neurological conditions, especially Alzheimer’s disease, suggest that impression of change could be a valid measure, as its ecological validity proves to be higher than in other complex tasks. Patients, as well as clinicians and more specifically caregivers, must provide information about the effects of treatment on cognition. Measures of daily living functioning, quality of life and caregivers’ burden should also be considered, especially when testing severe cognitively impaired patients. AChEI could constitute a promising treatment for cognitive impairment in MS, if this therapeutic approach is validated through large clinical trials.
References [1] Fisher JS. Cognitive impairment in multiple sclerosis. In: Cook SD, editor. Handbook of multiple sclerosis. 3rd. edn. New York’ Marcel Dekker; 2001. p. 33 – 255. [2] Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis. A review of recent developments. Curr Opinion Neurol 2003;16:283 – 8. [3] Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis: I. Frequency, patterns, and prediction. Neurology 1991;41:685 – 91. [4] Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis: II. Impact on employment and social functioning. Neurology 1991;41:692 – 6. [5] Spencer CM, Noble S. Rivastigmine. A review of its use in Alzheimer’s disease. Drugs Aging 1998;13:391 – 411. [6] McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000;356: 2031 – 6. [7] Werber EA, Rabey JM. The beneficial effect of cholinesterase inhibitors on patients suffering from Parkinson’s disease and dementia. J Neural Transm 2001;108:1319 – 25. [8] Kumar V, Anand R, Messina J, Hartman R, Veach J. An efficacy and safety analysis of Exelon in Alzheimer’s disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7:159 – 69. [9] Masanic CA, Bayley MT, VanReekum R, Simard M. Open-label study of donepezil in traumatic brain injury. Arch Phys Med Rehabil 2001;82:896 – 901. [10] Pozzilli C, Passafiume D, Bernardi S, Pantano P, Incoccia C, Bastianello S, et al. SPECT, MRI and cognitive functions in multiple sclerosis. J Neurol Neurosurg Psychiatry 1991;54:110 – 5. [11] Paulesu E, Perani D, Fazio F, Comi G, Pozzilli C, Martinelli V, et al. Functional basis of memory impairment in multiple sclerosis: a [18F]FDG PET study. Neuroimage 1996;4:87 – 96. [12] Leo GJ, Rao SM. Effects of intravenous physostigmine and lecithin on memory loss in multiple sclerosis: report of a pilot study. J Neurol Rehab 1988;2:123 – 9. [13] Unverzagt FW, Rao SM, Antuono PG. Oral physostigmine in the treatment of memory loss in multiple sclerosis (MS). J Clin Exp Neuropsychol 1991;131:74. [14] Parry AM, Scott RB, Palace J, Smith S, Matthews PM. Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain 2003;126:2750 – 60.
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181 [15] Greene YM, Tariot PN, Wishart H, Cox C, Holt CJ, Schwid S, et al. A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. J Clin Psychopharmacol 2000;20:350 – 6. [16] Rorie KD, Stump DA, Jeffery DR, Winston Salem NC. Effects of donepezil on cognitive function in patients with multiple sclerosis. Neurology 2001;56(Suppl. 3):A99. [17] Bosca` I, Bueno A, Gadea M, Casanova B, Coret F. Donepezile and cognitive impairment in multiple sclerosis: a double-blind pilot study. Mult Scler 2004;10(Suppl. 2):S150. [18] Decoo D, on behalf of the MS Rehab Study Group. Effects of donepezil in multiple sclerosis: a single-centre trial. Mult Scler 2004;10(Suppl. 2):S150.
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[19] Krupp LB, Christodoulou C, Melville P, Scherl WF, MacAllister WS, Elkins LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004;63:1579 – 85. [20] Christodoulou C, Krupp LB, Brook S, Dwyer MG, Melville P, Scherl WF, et al. Relation to cognitive dysfunction to multiple neuroimaging measures over 24 weeks. Neurology 2005;64(Suppl. 1):S26003. [21] Porcel J, Borra`s C, Are´valo MJ, Sa´nchez A, Cucala M, Falip M, et al. Design of a clinical trial to study the efficacy and safety of Exelon\ (rivastigmine) in multiple sclerosis patients with cognitive disorders. Mult Scler 2003;9:S143. [22] Rao SM. White matter disease and dementia. Brain Cogn 1996;31: 250 – 68.
Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis J. Porcel *, X. Montalban 2a Planta EUI, Unitat de Neuroimmunologia Clı´nica, Hospital Universitari Vall d’Hebron, Ps. Vall d’Hebron 119-129, 08035, Barcelona, Spain Received 4 April 2005; received in revised form 27 June 2005; accepted 8 July 2005 Available online 3 May 2006
Abstract Neuropsychological impairment is a common manifestation in multiple sclerosis (MS) and is found in 40 – 60% of patients. The pattern of cognitive impairment in MS is characterized by difficulties in recent memory, sustained attention, executive functions and information processing speed. These cognitive deficits have a significant impact on the patients’ daily activities. However, there is no specific treatment available at present for cognitive disorders in MS patients. Treatment with acetylcholinesterase inhibitors (AChEI) has shown a positive effect on cognitive functions of patients with Alzheimer’s disease and other conditions such as Lewy Body dementia, subcortical vascular dementia and Parkinson’s disease. In this paper we review the results from studies and clinical trials aiming to demonstrate that AChEI could be a potential treatment for cognitive disorders in MS patients. Finally, we discuss future issues to take into consideration for AChEI treatments in the context of MS. D 2006 Elsevier B.V. All rights reserved. Keywords: Multiple sclerosis; Anticholinesterasics; Cognitive impairment; Rivastigmine; Donezepil
1. Introduction Neuropsychological studies have extensively described the presence of cognitive dysfunction in multiple sclerosis (MS) patients [1] that may result from the disruption of cortical and subcortical pathways as a consequence of demyelination and axonal transection. About half of the diagnosed patients will experience problems with their memory, concentration, attention and other cognitive capacities in the course of the illness [2,3]. Cognitive impairment, ranging from mild deficit to dementia, clearly impacts on the patient’s life. Rates of unemployment are high among patients with cognitive impairment, social isolation is greater and the need for more home
* Corresponding author. Tel.: +34 932746202; fax: +34 932746084. E-mail address: [email protected] (J. Porcel). 0022-510X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.07.021
assistance clearer than for patients without cognitive disorders [4]. Much of this deficit causes trouble to the patients and their families. No specific treatment is yet available for cognitive disorders in MS. One possible treatment could be based on the use of acetylcholinesterase inhibitors (AChEI), which have shown efficacy not only in Alzheimer’s disease [5] but also in other cognitive disorders such as dementia with Lewy bodies [6], Parkinson’s disease [7], vascular dementia [8] and traumatic brain injury [9]. AChEI may therefore represent a potential therapeutic option for impaired cognitive status in MS because the cholinergic system is probably affected in the course of the disease and can underlie the cognitive deficits seen in those patients. Further reasons to favor AChEI in the treatment of MS patients lie in the hypothesis that several structures associated with the cholinergic system, such as the temporal lobe, the hippocampus and the thalamus, could be related to cognitive impairment in MS, especially memory [10,11].
178
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181
2. AchEI to treat cognitive impairment in MS: pilot studies Early pilot studies, conducted on small populations of MS patients, have shown that physostigmine and lecithin can improve memory, but their side effects have limited their use [12,13]. The effect of AChEI has also been very recently evidenced in MS, using fMRI [14]. In this study, brain activation patterns have been shown to be different between MS patients and controls before treatment, but tend to normalize after administration of rivastigmine. The authors concluded that functional plasticity was an acute response to AChEI.
3. Donepezil to treat cognitive impairments in MS: clinical trials Several studies have addressed the effect of donepezil on cognitive dysfunction in MS patients (Table 1). In 2000, Greene et al. [15] reported the results of an open trial with donepezil administered over 12 weeks to 17 moderate-to-severe cognitively impaired patients (Mini Mental Status Examination (MMSE) equal or below 25 points). Patients were evaluated by means of a comprehensive neuropsychological battery including measures of impression of change, behavioral symptoms and activities of daily living (Table 2). Efficacy parameters were obtained at baseline, and after 4 and 12 weeks. The authors observed an improvement in several cognitive domains and behavioral aspects. The positive effect of the drug on cognition was coupled by good tolerability; only one case of spasticity was related to the administration of donepezil. Although preliminary and with obvious methodological limitations, these results emphasized the importance of conducting large clinical trials to test the possible role of AChEI in the treatment of MS cognitive disorders. Rorie et al. [16] designed a randomized, double blind, placebo-controlled, crossover trial. Inclusion criteria of MS patients were based on memory complaints and objective cognitive dysfunction assessed by the examiner. Assessment, including several neuropsychological tasks (Table 2), was performed at baseline and after 6 weeks of treatment with donepezil. After a 2-week washout period, patients
were then crossed over to placebo or donepezil and retested after another 6 weeks of treatment. Thirty-two patients were enrolled in this trial and 25 completed the whole study protocol. The authors failed to find a treatment effect on cognition and concluded that donepezil may not be useful to treat cognitive problems in MS. No indication about adverse effects could be derived from this report [16]. In the study of Bosca` et al. [17], 27 patients with secondary progressive MS were enrolled in a 6-month, randomized, double blind, placebo-controlled trial and assessed with a comprehensive neuropsychological battery (Table 2) at baseline and 6 months after treatment initiation. Cognitive status of patients was not reported. Seven patients (4 in the placebo group and 3 in the treatment arm) withdrew from the study due to side effects. The authors concluded that the drug was well tolerated, but due to the small sample size it was difficult to establish the efficacy of the treatment. In fact only a slight improvement in semantic language fluency was observed. Decoo et al. [18] conducted a 6-month, randomized, double blind, placebo-controlled, crossover trial. Fifty MS patients with mild to moderate cognitive deficit, defined as a score below two standard deviations in the PASAT performance and a score equal to or above 27 points in the MMSE were included. Neuropsychological assessment (Table 2) was performed at baseline, 3 and 6 months after treatment initiation. Only four patients gave up the trial due to adverse effects (3 in the treatment group because of gastrointestinal problems and 1 patient in the placebo group because of headache). Efficacy measures showed better scores during the donepezil period in the psychosocial dimension of the Sickness Impact Profile, and in different measures of executive function (Stroop test, verbal fluency and Wisconsin Card Sorting Test). Krupp et al. [19] have reported the results of the largest study published to date. It consisted in a 24-week, randomized, double blind, placebo-controlled trial with donepezil to study MS patients who fulfilled the following inclusion criteria: mild memory impairment and no severe cognitive impairment (a score of at least 0.5 standard deviations below normative data adjusted for age and sex in a memory task (Rey Auditory Verbal Learning Test) with a score equal to or above 26 in the MMSE), and no severe depression symptoms (scores in the Montgomery Ashberg Depression Scale equal to or below 14 points). Measures
Table 1 Summary of the studies described
Greene et al., 2000 Rorie et al., 2001 Bosca` et al., 2004 Decoo et al., 2004 Krupp et al., 2004
Patients cognitive status
Anticholinesterasics Tolerability
Cognitive effect
n = 17, n = 32, n = 27, n = 50, n = 69,
Well tolerated Not indicated Well tolerated Well tolerated Well tolerated
Positive effect No effect Positive effect Positive effect Positive effect
MMSE r 25 Complaints of memory loss Not indicated Mild to moderate At least mild memory deficit
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181 Table 2 Neuropsychological tests included in AChEI studies with MS patients Study (author, year)
Neuropsychological assessment
Greene et al., 2000
Primary outcome measures Mini-Mental Status Examination Hopkins Verbal Learning Test Clinical Global Impression of Change Secondary outcome measures Brief Test of Attention Digit Span Test Boston Naming Test Controlled Oral Word Association Test Motor-Free Visual Perception Test Mattis Dementia Rating Scale Neuropsychiatric Inventory Questionnaire Logical Memory (immediate and delayed) Paired Associate Learning Verbal Fluency Verbal Learning Letter Cancellation Trail Making Test Visual Reaction Time Mini-Mental Status Examination Verbal IQ (WAIS III) Set Test Controlled Oral Word Association Test Weschler Memory Scale Wisconsin Card Sorting Test Trail Making Test Stroop Test Boston Test Benton (Form D) Beck Depression Scale Hamilton Anxiety Scale National Adult Reading Test Word Fluency Auditory Verbal Learning Test Stroop Color Word Test Hooper Visual Organization Test Wisconsin Card Sorting Test Dysexecutive Questionnaire Sickness Impact Profile Primary outcome measure Selective Reminding Test (total recall) Secondary outcome measures 10/36 Spatial Recall Test Symbol Digit Modalities Test Paced Auditory Serial Addition Test Controlled Oral Word Association Tower of Hanoi Simple Visual Reaction Time Symbol Digit Modalities Test Paced Auditory Serial Addition Test Continuous Performance Test Rey Auditory-Verbal Learning Test Rey-Osterrieth Complex Figure Test Digit Subtest (WAIS III) Figural Memory (WMS-R) Trail Making Test Wisconsin Card Sorting Test Stroop Test Set Test Controlled Oral Word Association Test Vocabulary Subtest (WAIS III) Hospital Anxiety and Depression Scale
Rorie et al., 2001
Bosca` et al., 2004
Decoo et al., 2004
Krupp et al., 2004
Porcel et al., 2003
179
Table 2 (continued) Study (author, year)
Neuropsychological assessment
Porcel et al., 2003
SF-36 Neuropsychiatric Inventory Questionnaire Test of Reporter Clinical Global Impression of Change
were obtained at baseline in 69 patients then randomized to donepezil (35 patients) or placebo (34 patients) groups. After 24 weeks of treatment, participants were reassessed. Seven patients (2 because of side effects) in the donepezil arm and 5 patients (3 because of side effects) in the placebo group were lost to follow-up. The primary outcome measure was change in the total recall of the verbal memory task included in the Brief Repeatable Battery of Neuropsychological Tests. The other cognitive tasks of the battery and the Tower of Hanoi test were secondary outcomes, in addition to the clinician’s impression of cognitive change and the patient’s self-impression of memory change (Table 2). The results showed that treated patients verbal memory improved in about 10% from mean baseline. Other secondary measures related to verbal memory improved significantly more in the treated group while the other cognitive variables did not differ between groups. Statistically significant differences were also found in both patients and clinicians impressions of change; more treated patients reported improvement in memory compared with the placebo group (66% vs. 32%) and more clinicians observed cognitive improvement in the donepezil arm when compared with the placebo group (54% vs. 29%). Most common adverse effects were the reporting of abnormal dreaming during sleep (34%), diarrhoea (26%), nausea (26%), spasticity (17%) and numbness (17%). Because groups only statistically differed in the reporting of abnormal dreaming, the authors concluded that the drug was relatively well tolerated. Recently, the authors have reported the results of the MRI study, which included 26 MS patients, performed within the donepezil clinical trial [20]. The report concludes that longitudinal brain atrophy was the only measure that correlated with change in cognitive performance over a 6month period. Interestingly, the authors did not observe differences in the MRI measures between the medication groups. To summarize, current data from the literature indicates that AChEI may be useful to treat cognitive deficit present in MS patients; with good tolerability, despite some otherwise usual side effects.
4. Rivastigmine to treat cognitive impairment in MS: clinical trials We are currently conducting a clinical trial at our MS unit to test the efficacy and safety of rivastigmine, another AChEI, to treat patients with severe cognitive impairment who fulfill the criteria of dementia according to the
180
J. Porcel, X. Montalban / Journal of the Neurological Sciences 245 (2006) 177 – 181
Diagnostic and Statistical Manual of Mental Disorders-IV or the Clinical Dementia Rating Scale (stage 1 or higher) [21]. The study is a 36-week, randomized, double blind, placebo-controlled trial including a 12-week screening period, a baseline period, a dose-escalation period (from baseline to week 24), a maintenance period (from week 24 to week 36) and a post-treatment period (from week 36 on to week 48). A neuropsychologist blinded as to the patients evolution throughout the study as well as to the presence of adverse effects, assesses patients with a comprehensive neuropsychological battery (Table 2). To control for practice effects, a screening assessment is included together with the use of tasks with alternate forms. Whenever this was not possible, the specific task was limited to the baseline and the end-of-treatment visits. Because the included patients have severe cognitive impairment, participation in the study requires the close collaboration of a caregiver who is willing to take on responsibility for monitoring treatment compliance as well as the patient’s condition throughout the study providing information on the efficacy variables. In this sense, we include the assessment of behavioral aspects using the Neuropsychiatric Inventory Questionnaire and the impression of cognitive change by the caregiver using the Test of Reporter. This is the first study to test rivastigmine, a new AchEI with selectivity for the hippocampus and cortex [5] with previously proven efficacy on cognition in Alzheimer’s disease patients [5]. With the aim to detect a positive drug effect, the study protocol covers all the cognitive areas where impairment could be found in MS patients. The inclusion of caregivers’ reportings will also aid to distinguish between neuropsychological performance and change occurring in real life. Finally, the results of this study will increase knowledge on the effect of AchEI in demented MS patients, which stands approximately at 20% to 30% of the patients with cognitive impairment [22].
5. Discussion and conclusion In the recent past, there has been an increasing interest in testing new therapeutic approaches to cognitive dysfunction in MS. As suggested by the studies reviewed in this paper, AChEI may be a valid candidate. Now, it would be necessary to perform large multicentre trials to confirm these results. Design of new studies should also aim to find answers to other issues related with efficacy and safety at long term as well as withdrawal effects and treatment duration. However, to begin with AChEI research in MS needs to approach two key questions. First, what patients will be treated? And second, what outcome measures will be used? Because MS cognitive disorders comprise a wide spectrum from mild deficit to dementia, we need to define what patients will most benefit from treatment and hence
whether it is more appropriate to treat a patient upon early cognitive complaints or to defer until cognitive impairment significantly impacts in daily living. It is also necessary to identify useful outcome measures. Results from the studies reviewed above and from other neurological conditions, especially Alzheimer’s disease, suggest that impression of change could be a valid measure, as its ecological validity proves to be higher than in other complex tasks. Patients, as well as clinicians and more specifically caregivers, must provide information about the effects of treatment on cognition. Measures of daily living functioning, quality of life and caregivers’ burden should also be considered, especially when testing severe cognitively impaired patients. AChEI could constitute a promising treatment for cognitive impairment in MS, if this therapeutic approach is validated through large clinical trials.
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