- Email: [email protected]
Donepezil for memory impairment in multiple sclerosis
Reflection and Reaction
identified, and the role of behavior and activity limitations in modifying those risks assessed”. Although in the US study and in the European study a small risk of injuries could be expected based on the restrictions people with epilepsy may have in daily living activities, one can reasonably conclude that most accidents occur in patients with uncontrolled epilepsy and that epilepsy in pharmacological remission carries only a mild to moderate risk of accidents.
I have no conflicts of interest. 1
2
3
4 5
Ettore Beghi Epilepsy Center, University of Milano Bicocca, Monza, and Laboratory of Neurological Disorders, Mario Negri Institute, Milano, Italy [email protected]
6 7
Lawn ND, Bamlet WR, Radhakrishnan K, O’Brien PC, So EL. Injuries due to seizures in persons with epilepsy: a population-based study. Neurology 2004; 63: 1565–70. Beghi E, Cornaggia C, for the Risk in Epilepsy Study Group. Epilepsy and everyday life risks: a case-referent study—rationale, study design, and preliminary results. Neuroepidemiology 1997; 16: 207–16. Beghi E, Cornaggia C, RESt-1 Group. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002; 43: 1076–83. Nakken KO, Lossius R. Seizure-related injuries in multihandicapped patients with therapy-resistant epilepsy. Epilepsia 1993; 34: 836–40. Buck D, Baker GA, Jacoby A, Smith DF, Chadwick DW. Patients’ experience of injury as a results of epilepsy. Epilepsia 1997; 38: 439–44. Begley CE, Beghi E. The economic cost of epilepsy: a review of the literature. Epilepsia 2002; 43: 3–9. Berg AT. Are patients with epilepsy at high risk for injury? Neurology 2004; 63: 1549.
Donepezil for memory impairment in multiple sclerosis In the past two decades, clinicians have become more aware of the profound effect of cognitive impairment in multiple sclerosis (MS). 40–65% of patients with MS have cognitive impairment, with involvement of memory, sustained attention, and information processing speed.1 Cognitive impairment can be detected in the early stages of MS, occurs in all disease subtypes, and typically progresses over time.2 In MRI studies, deficits relate to brain-lesion burden and atrophy.1 Cognitive dysfunction can have a large effect on a patient’s quality of life and can influence role fulfilment in work and social life independently of physical disability.2 Despite its frequency and impact, treatment strategies for cognitive impairment in MS are in their infancy. Diseasemodifying drugs—such as interferon beta and glatiramer acetate—may prevent or reduce the progression of cognitive dysfunction by delaying the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial.3 Small trials with amantadine, pemoline, fampridine, and 3,4-diaminopyridine provided mainly negative results.4 Few studies of non-pharmacological interventions with cognitive rehabilitation have used an experimental approach. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer’s disease (AD)—such as donepezil, rivastigmine, and galantamine—have recently been tested in other cognitive disorders, including MS. Cholinergic deficits in MS might derive from disruption of cholinergic pathways and impaired axonal transport of acetylcholine owing to demyelination and axonal transection. Additional mechanisms of action may include increases in cerebral glucose utilisation. Most pilot trials with AChEI in MS have provided promising results,5 and the donepezil study recently published by Krupp and colleagues5 is a major development. In this single-centre, randomised, double-blind trial, 69 patients with MS with initial cognitive impairment were 72
treated with donepezil (10 mg daily) or placebo for 24 weeks. 65% of those treated with donepezil, compared with 50% of those given placebo, showed significant improvement on a test of verbal learning and memory, representing the study’s primary endpoint. Moreover, on the basis of the judgement of patients and clinicians, there was significantly greater memory improvement in the donepezil group. The drug was generally well tolerated, with the exception that unusual dreams occurred more frequently in donepezil-treated (34·3%) than in placebo-treated (8·8%) patients. Although these results are encouraging, possible limitations of the study must be taken into account. On the whole, the therapeutic effects, although significant, were not particularly impressive: a mean improvement of four words is an improvement of only about 10% from mean baseline ability. Patients treated with donepezil did not have significant improvements on other cognitive tasks or overall cognitive score. Perhaps more interesting was the benefit reported by patients and clinicians, suggesting that treatment effects were clinically detectable and perceived in everyday functioning. However, patients’ and clinicians’ impressions were scarcely formalised—they were graded “no change”, “worse”, or “improved”. The study included no assessment by carers who may provide more reliable information on a patient’s cognitive status. Moreover, the “evaluating” physician being the “treating” physician may have introduced a bias. The sample size was small, and randomisation resulted in an unequal representation of patients for disease course and disability level, although the results were confirmed after controlling for these factors. Furthermore, results refer to a selected sample of patients with initial cognitive impairment and cannot be easily extrapolated to the general population of patients with MS. For instance, patients with severe disability, clinical depression, or mini-mental state examination scores below 26 were excluded. Finally, reported http://neurology.thelancet.com Vol 4 February 2005
Reflection and Reaction
side-effects—such as abnormal dreams (34%), diarrhoea (26%), nausea (26%), spasticity (17%) and numbness (17%)—were more common than in AD trials. Therefore, future studies should probably test lower doses. As Krupp and colleagues recognise, the results need confirmation in larger-scale multicentre trials. In addition, because MS evolves over decades, a 24 week follow-up is clearly too short to appreciate the real effect of the therapy. Assessment of the efficacy in the long-term is therefore a critical issue. Future studies should also address possible withdrawal effects, long-term efficacy and safety, and costeffectiveness. Moreover, comparative trials of different AChEI and studies of alternatives should be developed. Until these questions are answered, this study can help clinicians in everyday practice to better assess cost/benefit ratios of offlabel use of AChEI in MS.
Maria Pia Amato Department of Neurology, University of Florence, Italy mariapia.amato@unifi.it I have received research grants or honoraria from Serono, Dompé Biotec, Shering, and Aventis Pharma. 1 2
3 4 5
Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol 2003; 16: 283–88. Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in earlyonset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 2001; 58: 1602–06. Fisher JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Ann Neurol 2000; 48: 885–92. Amato MP, Zipoli V. Clinical management of cognitive impairment in multiple sclerosis: a review of current evidence. Int MS J 2003; 10: 70–83. Krupp LB, Christodoulou C, Melville RN, Scherl WF, McAllister WS, Elkin LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63: 1579–85.
Prevention of in-hospital mortality after stroke
http://neurology.thelancet.com Vol 4 February 2005
consciousness. High intracranial pressure and symptomatic intracranial haemorrhage were associated with 47·7% and 29·2% of in-hospital deaths, respectively. Another measure of stroke mortality is long-term survival. In a population-based study with virtually complete
Gusto/Science Photo Library
Heuschmann and colleagues1 recently reported predictors of in-hospital mortality after ischaemic stroke from the German Stroke Registers Study Group (ADSR) cohort. The analysis includes 13 440 patients with ischaemic stroke admitted in 1 year to 104 participating hospitals. Patients were excluded if they were treated with thrombolysis or had a length of stay over 25 days. Overall in-hospital mortality was 4·9%. Predictors of mortality for women included old age, severity of stroke (defined by number of neurological deficits), and atrial fibrillation. In men, diabetes and previous stroke were also associated with mortality. Pneumonia and high intracranial pressure accounted for most deaths (31·2% and 28·6%, respectively). These data can be compared with other non-population based stroke registries. In the Lausanne Stroke Registry2 there was a 3·7% in-hospital mortality after first ischaemic stroke, and independent predictors of mortality included impaired consciousness on admission, progressive neurological worsening, limb weakness, left ventricular hypertrophy, previous cardiac arrhythmia, and previous transient ischaemic attack. The presumed cause of death was the index stroke in 40%, pulmonary complications in 11%, and cardiac complications in 7%.2 These data from large, non-population-based cohorts should be put in the context of other data to give a more complete picture of stroke mortality. Additional factors to consider include the mortality among the small proportion of patients with ischaemic stroke treated with thrombolysis, population-based data on long-term and cause-specific mortality, and the potential of stroke mechanism as a predictor of stroke mortality. The ADSR study group3 data on 1796 patients (3·2% of all patients) who received thrombolysis in 3 years showed 10% mortality. Risk of in-hospital death after thrombolysis was independently related to old age and changed level of
Non-neurological factors become important causes of in-hospital mortality soon after stroke
ascertainment of all strokes during 1975–89, overall survival after first stroke was 86·1% at 30 days and 47% at 5 years.4 Independent predictors of mortality included old age, congestive heart failure, persistent atrial fibrillation, ischaemic heart disease (all at presentation), and recurrent stroke. Clarification of long-term cause-specific mortality after stroke can also be useful in suggesting means of improving survival after stroke.5 In a population-based study, within the 73
identified, and the role of behavior and activity limitations in modifying those risks assessed”. Although in the US study and in the European study a small risk of injuries could be expected based on the restrictions people with epilepsy may have in daily living activities, one can reasonably conclude that most accidents occur in patients with uncontrolled epilepsy and that epilepsy in pharmacological remission carries only a mild to moderate risk of accidents.
I have no conflicts of interest. 1
2
3
4 5
Ettore Beghi Epilepsy Center, University of Milano Bicocca, Monza, and Laboratory of Neurological Disorders, Mario Negri Institute, Milano, Italy [email protected]
6 7
Lawn ND, Bamlet WR, Radhakrishnan K, O’Brien PC, So EL. Injuries due to seizures in persons with epilepsy: a population-based study. Neurology 2004; 63: 1565–70. Beghi E, Cornaggia C, for the Risk in Epilepsy Study Group. Epilepsy and everyday life risks: a case-referent study—rationale, study design, and preliminary results. Neuroepidemiology 1997; 16: 207–16. Beghi E, Cornaggia C, RESt-1 Group. Morbidity and accidents in patients with epilepsy: results of a European cohort study. Epilepsia 2002; 43: 1076–83. Nakken KO, Lossius R. Seizure-related injuries in multihandicapped patients with therapy-resistant epilepsy. Epilepsia 1993; 34: 836–40. Buck D, Baker GA, Jacoby A, Smith DF, Chadwick DW. Patients’ experience of injury as a results of epilepsy. Epilepsia 1997; 38: 439–44. Begley CE, Beghi E. The economic cost of epilepsy: a review of the literature. Epilepsia 2002; 43: 3–9. Berg AT. Are patients with epilepsy at high risk for injury? Neurology 2004; 63: 1549.
Donepezil for memory impairment in multiple sclerosis In the past two decades, clinicians have become more aware of the profound effect of cognitive impairment in multiple sclerosis (MS). 40–65% of patients with MS have cognitive impairment, with involvement of memory, sustained attention, and information processing speed.1 Cognitive impairment can be detected in the early stages of MS, occurs in all disease subtypes, and typically progresses over time.2 In MRI studies, deficits relate to brain-lesion burden and atrophy.1 Cognitive dysfunction can have a large effect on a patient’s quality of life and can influence role fulfilment in work and social life independently of physical disability.2 Despite its frequency and impact, treatment strategies for cognitive impairment in MS are in their infancy. Diseasemodifying drugs—such as interferon beta and glatiramer acetate—may prevent or reduce the progression of cognitive dysfunction by delaying the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial.3 Small trials with amantadine, pemoline, fampridine, and 3,4-diaminopyridine provided mainly negative results.4 Few studies of non-pharmacological interventions with cognitive rehabilitation have used an experimental approach. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer’s disease (AD)—such as donepezil, rivastigmine, and galantamine—have recently been tested in other cognitive disorders, including MS. Cholinergic deficits in MS might derive from disruption of cholinergic pathways and impaired axonal transport of acetylcholine owing to demyelination and axonal transection. Additional mechanisms of action may include increases in cerebral glucose utilisation. Most pilot trials with AChEI in MS have provided promising results,5 and the donepezil study recently published by Krupp and colleagues5 is a major development. In this single-centre, randomised, double-blind trial, 69 patients with MS with initial cognitive impairment were 72
treated with donepezil (10 mg daily) or placebo for 24 weeks. 65% of those treated with donepezil, compared with 50% of those given placebo, showed significant improvement on a test of verbal learning and memory, representing the study’s primary endpoint. Moreover, on the basis of the judgement of patients and clinicians, there was significantly greater memory improvement in the donepezil group. The drug was generally well tolerated, with the exception that unusual dreams occurred more frequently in donepezil-treated (34·3%) than in placebo-treated (8·8%) patients. Although these results are encouraging, possible limitations of the study must be taken into account. On the whole, the therapeutic effects, although significant, were not particularly impressive: a mean improvement of four words is an improvement of only about 10% from mean baseline ability. Patients treated with donepezil did not have significant improvements on other cognitive tasks or overall cognitive score. Perhaps more interesting was the benefit reported by patients and clinicians, suggesting that treatment effects were clinically detectable and perceived in everyday functioning. However, patients’ and clinicians’ impressions were scarcely formalised—they were graded “no change”, “worse”, or “improved”. The study included no assessment by carers who may provide more reliable information on a patient’s cognitive status. Moreover, the “evaluating” physician being the “treating” physician may have introduced a bias. The sample size was small, and randomisation resulted in an unequal representation of patients for disease course and disability level, although the results were confirmed after controlling for these factors. Furthermore, results refer to a selected sample of patients with initial cognitive impairment and cannot be easily extrapolated to the general population of patients with MS. For instance, patients with severe disability, clinical depression, or mini-mental state examination scores below 26 were excluded. Finally, reported http://neurology.thelancet.com Vol 4 February 2005
Reflection and Reaction
side-effects—such as abnormal dreams (34%), diarrhoea (26%), nausea (26%), spasticity (17%) and numbness (17%)—were more common than in AD trials. Therefore, future studies should probably test lower doses. As Krupp and colleagues recognise, the results need confirmation in larger-scale multicentre trials. In addition, because MS evolves over decades, a 24 week follow-up is clearly too short to appreciate the real effect of the therapy. Assessment of the efficacy in the long-term is therefore a critical issue. Future studies should also address possible withdrawal effects, long-term efficacy and safety, and costeffectiveness. Moreover, comparative trials of different AChEI and studies of alternatives should be developed. Until these questions are answered, this study can help clinicians in everyday practice to better assess cost/benefit ratios of offlabel use of AChEI in MS.
Maria Pia Amato Department of Neurology, University of Florence, Italy mariapia.amato@unifi.it I have received research grants or honoraria from Serono, Dompé Biotec, Shering, and Aventis Pharma. 1 2
3 4 5
Bobholz JA, Rao SM. Cognitive dysfunction in multiple sclerosis: a review of recent developments. Curr Opin Neurol 2003; 16: 283–88. Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in earlyonset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 2001; 58: 1602–06. Fisher JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Ann Neurol 2000; 48: 885–92. Amato MP, Zipoli V. Clinical management of cognitive impairment in multiple sclerosis: a review of current evidence. Int MS J 2003; 10: 70–83. Krupp LB, Christodoulou C, Melville RN, Scherl WF, McAllister WS, Elkin LE. Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology 2004; 63: 1579–85.
Prevention of in-hospital mortality after stroke
http://neurology.thelancet.com Vol 4 February 2005
consciousness. High intracranial pressure and symptomatic intracranial haemorrhage were associated with 47·7% and 29·2% of in-hospital deaths, respectively. Another measure of stroke mortality is long-term survival. In a population-based study with virtually complete
Gusto/Science Photo Library
Heuschmann and colleagues1 recently reported predictors of in-hospital mortality after ischaemic stroke from the German Stroke Registers Study Group (ADSR) cohort. The analysis includes 13 440 patients with ischaemic stroke admitted in 1 year to 104 participating hospitals. Patients were excluded if they were treated with thrombolysis or had a length of stay over 25 days. Overall in-hospital mortality was 4·9%. Predictors of mortality for women included old age, severity of stroke (defined by number of neurological deficits), and atrial fibrillation. In men, diabetes and previous stroke were also associated with mortality. Pneumonia and high intracranial pressure accounted for most deaths (31·2% and 28·6%, respectively). These data can be compared with other non-population based stroke registries. In the Lausanne Stroke Registry2 there was a 3·7% in-hospital mortality after first ischaemic stroke, and independent predictors of mortality included impaired consciousness on admission, progressive neurological worsening, limb weakness, left ventricular hypertrophy, previous cardiac arrhythmia, and previous transient ischaemic attack. The presumed cause of death was the index stroke in 40%, pulmonary complications in 11%, and cardiac complications in 7%.2 These data from large, non-population-based cohorts should be put in the context of other data to give a more complete picture of stroke mortality. Additional factors to consider include the mortality among the small proportion of patients with ischaemic stroke treated with thrombolysis, population-based data on long-term and cause-specific mortality, and the potential of stroke mechanism as a predictor of stroke mortality. The ADSR study group3 data on 1796 patients (3·2% of all patients) who received thrombolysis in 3 years showed 10% mortality. Risk of in-hospital death after thrombolysis was independently related to old age and changed level of
Non-neurological factors become important causes of in-hospital mortality soon after stroke
ascertainment of all strokes during 1975–89, overall survival after first stroke was 86·1% at 30 days and 47% at 5 years.4 Independent predictors of mortality included old age, congestive heart failure, persistent atrial fibrillation, ischaemic heart disease (all at presentation), and recurrent stroke. Clarification of long-term cause-specific mortality after stroke can also be useful in suggesting means of improving survival after stroke.5 In a population-based study, within the 73