- Email: [email protected]
Constraint-induced movement therapy translated into practice
Comment
used for the first time in ALS in a study investigating lithium carbonate,9 in response to a report describing the potential benefits with lithium that triggered a frenzy of hope in the ALS community. The use of historical controls was well justified in the case of lithium because various randomised controlled trials with lithium were already on the horizon. Yet nearly everyone agrees that studies with historical controls are useful only for probing of possibilities, and that any possible efficacy shown should be followed by appropriate randomised controlled trials. Because the ALS community has already accumulated a large amount of data, meaningful historical control-based studies might become a viable option in the future,10 but how to select historical controls in each trial is still an issue of fundamental importance. Although the DiPALS investigators fully discuss possible reasons for poor outcomes with non-invasive ventilation and diaphragm pacing in their report,8 the mechanisms of why this happened could have been investigated with use of periodical nocturnal pulse oximetry and, in selected patients, polysomnograms could have been obtained. This information would have helped us learn how to manage non-invasive ventilation in the future. Our experience with diaphragm pacing raises several important questions of how to undertake ALS clinical trials properly and from early stages. There is a strong need for new international guidelines for clinical trials of ALS, which would detail how to undertake more effective and efficient clinical trials in the future, especially because the current guidelines are already 16 years old.11
Hiroshi Mitsumoto Eleanor and Lou Gehrig MDA/ALS Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032 USA [email protected] I declare no competing interests. Copyright © Mitsumoto et al. Open Access article distributed under the terms of CC BY. 1
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3
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7 8
9
10
11
Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009; 73: 1227–33. Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol 2012; 19: 360–75. Atkeson AD, RoyChoudhury A, Harrington-Moroney G, Shah B, Mitsumoto H, Basner RC. Patient-ventilator asynchrony with nocturnal noninvasive ventilation in ALS. Neurology 2011; 77: 549–55. Onders RP, DiMarco AF, Ignagni AR, Mortimer JT. The learning curve for investigational surgery—lessons learned from laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc 2005; 19: 633–37. Lechtzin N, Scott Y, Busse AM, Clawson LL, Kimball R, Wiener CM. Early use of non-invasive ventilation prolongs survival in subjects with ALS. Amyotroph Lateral Scler 2007; 8: 185–88. US Food and Drug Administration. Summary of safety and probably benefit (SSPB). 2011. http://www.accessdata.fda.gov/cdrh_docs/pdf10/ H100006b.pdf (accessed June 30, 2015). Fitzgerald S. Is a diaphragm pacing system for ALS ready for prime time? Neurology Today 2011; 11: 44–45. DiPALS Writing Committee, on behalf of the DiPALS Study Group Collaborators. Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. Lancet Neurol 2015; published online July 31. http://dx.doi.org/10.1016/S14744422(15)00152-0. Miller RG, Moore DH, Forshew DA, et al. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 2011; 77: 973–79. Küffner R, Zach N, Norel R, et al. Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression. Nat Biotechnol 2015; 33: 51–57. Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research. J Neurol Sci 1999; 169: 2–12.
Constraint-induced movement therapy translated into practice Constraint-induced movement therapy (CIMT) is the massed task practice of the affected limb with shaping techniques and constraint of the unaffected limb. CIMT and modified CIMT are the most empirically supported approaches to rehabilitation of the upper limbs after stroke. CIMT is a successful example1 of translating findings from basic research (from animal studies),2 to human clinical research (including phase 1–3 clinical trials)3,4 and practicewww.thelancet.com/neurology Vol 14 September 2015
based research (phase 3 randomised trials).5–7 In one study5 of 222 patients with stroke-related upper limb dysfunction, the effect of CIMT given before or after routine therapy was compared with standard care; however, without data from clinical practice, the assessment of CIMT or modified CIMT is arguably a conceptual investigation that will not benefit patients who receive regular therapy at clinics. In The Lancet Neurology, Anne Barzel and colleagues7 now report
Published Online July 29, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00183-0 See Articles page 893
869
Comment
their endeavours to validate the use of modified CIMT for neurorehabilitation in clinical practice. In a cluster-randomised controlled trial of homebased modified CIMT (home CIMT), 156 patients with upper-limb dysfunction after stroke were randomly assigned to receive 4 weeks of either home CIMT or standard therapy. Both groups of patients had 5 h of contact with a professional therapist but patients in the home CIMT group practiced exercises together with a non-professional coach (eg, a caregiver) in addition to the professional contact. Patients in the control group did not practice with a coach, and mandatory practice was not required beyond professional therapy time. The primary outcomes were self-perceived quality of movement, assessed by the Motor Activity Log (MALQOM), and objective performance time, assessed by the Wolf Motor Function Test (WMFT-PT). After 4 weeks of intervention, the self-perceived functional use of the affected limb had improved more in patients in the home CIMT group than in patients in the control group (MAL-QOM betweengroup difference in change from baseline 0·26, 95% CI 0·05–0·46; p=0·0156).7 Patients in the home CIMT group did additional hours of exercise wearing a resting glove to immobilise the non-affected hand, whereas patients in the control group did not report these data and possibly did not have as many extra hours of exercise or practice. Although home CIMT was found to improve the selfperceived use of the stroke-affected arm in daily life, the assessor-reported primary outcome measure was not improved by home CIMT (WMFT-PT between-group difference in change from baseline 2·65%, –17·94 to 28·40; p=0·8152). The secondary objective measures showed little clinically significant difference. Because the effects of home CIMT were limited to the selfreported outcomes, efforts towards augmenting the effectiveness of home CIMT on objective health-related outcomes are necessary in future studies. Anne Barzel and colleagues7 have translated CIMT into clinical practice for ambulatory care, and have adapted CIMT for use as a home-based programme with the intention of reducing use of resources by professionals and patients. However, this study was biased with respect to treatment dose, which is common for studies of CIMT, in that patients in the home CIMT group received hours of exercise and immobilising the 870
non-affected hand at home in addition to professional therapy whereas patients in the control group received therapy only during therapy contact either at home or at a practice. Future randomised controlled trials powered with a large number of patients who are representative of the general post-stroke population and a control group matched for dose and treatment location in regular routine practice will be essential to validate the effects of home-based modified CIMT.4 The patients in the home CIMT group relied on a nonprofessional coach to supervise their practice, limiting the applicability of this home protocol. The coach might not be able to recognise the patient’s compensatory strategies or impaired skills during task practice and provide immediate feedback, which might weaken the improvement of the patients receiving home CIMT. Telerehabilitation strategies allowing therapists to monitor or coach patient home-practice remotely might be a plausible way to implement home-based CIMT.8 Additionally, the cost-effectiveness of homebased modified CIMT in any form needs to be estimated and compared with that of conventional therapy. Bilateral priming, which involves bimanual, repetitive, and mirror-symmetric movement training, is an emerging strategy to accelerate motor recovery and promote functional improvements after stroke. Bilateral priming is suggested to enhance rebalancing of corticomotor excitability and is efficacious in augmenting upper limb recovery when done before upper limb therapy.9 To augment the treatment effects of modified CIMT, future research could investigate how the sequential combination of bilateral priming with modified CIMT affects stroke recovery. An important criterion for receiving CIMT or modified CIMT is the ability to extend one or more fingers of the affected limb, suggesting that these therapy forms are restricted to patients with a mild to moderate paresis of the limb. Portable and affordable upper-limb robotics could be integrated into CIMT or modified CIMT10 and implemented at home to enhance hand function during daily tasks in patients with severe movement deficits. Anne Barzel and colleagues have made an important contribution by adapting modified CIMT for stroke rehabilitation into clinical practice, and their findings should provide a basis for future stroke research. The issues regarding a control group that is matched by www.thelancet.com/neurology Vol 14 September 2015
Comment
dose and location, augmentation of treatment effects, expansion of applicability, and cost-effectiveness should be addressed in future research.
2 3
4
*Ching-Yi Wu, Ku-Chou Chang Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, College of Medicine, Chang Gung University, and Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan 333 (C-Y Wu); Division of Cerebrovascular Diseases, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, and Department of Senior Citizen Service Management, Yuh-Ing Junior College, Kaohsiung, Taiwan (K-C Chang) [email protected] C-YW and K-CC contributed equally to this Comment. C-YW and K-CC have received grants from the Ministry of Science and Technology, Chang Gung Memorial Hospital, and Healthy Aging Research Center at Chang Gung University. C-YW has also received grant from the National Health Research Institutes in Taiwan. 1
Westfall JM, Mold J, Fagnan L. Practice-based research—“blue highways” on the NIH roadmap. JAMA 2007; 297: 403–06.
5
6 7
8
9
10
Knapp HD, Taub E, Berman AJ. Movements in monkeys with deafferented forelimbs. Exp Neurol 1963; 7: 305–15. Koyama T, Sano K, Tanaka S, Hatanaka T, Domen K. Effective targets for constraint induced movement therapy for patients with upper-extremity impairment after stroke. NeuroRehabilitation 2007; 22: 287–93. Lin K, Wu C, Liu J, Chen Y, Hsu C. Constraint-induced therapy versus dose-matched control intervention to improve motor ability, basic/extended daily functions, and quality of life in stroke. Neurorehabil Neural Repair 2009; 23: 160–65. Wolf S, Winstein C, Miller J, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 2006; 296: 2095–104. Kwakkel G, Veerbeek JM, van Wegen EEH, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol 2015; 14: 224–34. Barzel A, Ketels G, Stark A, et al. Home-based constraint-induced movement therapy for patients with upper limb dysfunction after stroke (HOMECIMT): a cluster-randomised, controlled trial. Lancet Neurol 2015; published online July 29. http://dx.doi.org/10.1016/S1474-4422(15)00147-7. Brennan DM, Lum PS, Uswatte G, Taub E, Gilmore BM, Barman J. A telerehabilitation platform for home-based automated therapy of arm function. Conf Proc IEEE Eng Med Biol Soc 2011; 2011: 1819–22. Stinear CM, Barber PA, Petoe MA, Anwar S, Byblow WD. Bilateral priming accelerates recovery of upper limb function after stroke: a randomized controlled trial. Stroke 2014; 45: 205–10. Page SJ, Hill V, White S. Portable upper extremity robotics is as efficacious as upper extremity rehabilitative therapy: a randomized controlled pilot trial. Clin Rehabil 2013; 27: 494–50.
The definition of cryptogenic stroke or stroke of undetermined origin is affected by the current knowledge of the cause and pathogenesis of stroke and by the availability, comprehensiveness, quality, and timeliness of the ancillary investigations undertaken to discover the cause of the stroke.1 In The Lancet Neurology, Linxin Li and colleagues2 report findings from a population-based study of the burden, outcome, risk factors, and long-term prognosis of cryptogenic stroke in patients with a first transient ischaemic attack (TIA) or ischaemic stroke. They found that of 2555 first ischaemic events, 812 (32%) were cryptogenic. The study shows that the prognosis of cryptogenic stroke and the risk of recurrence are similar to those of large artery disease and small vessel disease. For example, death or dependency at 6 months was similar after cryptogenic stroke compared with large artery and small vessel subtypes combined (23% vs 27%; p=0·26), as was the 10-year risk of recurrence (32% vs 27%; p=0·91). Secondary stroke prevention must be similarly aggressive and appropriate in stroke with and without identified cause. The findings from this Article question the role of paroxysmal atrial fibrillation as the major cause of cryptogenic stroke, which contrasts with the present enthusiasm for the use of technology to detect www.thelancet.com/neurology Vol 14 September 2015
paroxysmal atrial fibrillation3 and for the possibility to prevent recurrent cryptogenic stroke with anticoagulants. The results of this study are especially important for health-care policy makers, because they show the burden of cryptogenic stroke, the rationale for a comprehensive investigation into the cause of every ischaemic stroke, and the need to provide stroke centres with access to the necessary ancillary diagnostic procedures. The diagnostic work up used in this study is unfortunately still not routinely used for every patient with ischaemic stroke, neither in the UK nor in mainland Europe. In developing countries, such diagnostic instruments are a distant mirage. This study has some limitations that hamper the translation of its results into routine practice: both TIAs and strokes were included, and the diagnosis of TIA can be erroneous even when done by a specialist; the causative investigation was incomplete, especially in phase 1; the search for paroxysmal atrial fibrillation was not pursued intensively; the investigation of the cause of stroke in recurrent strokes was incomplete; and the newest devices for prolonged heart rhythm monitoring were not used. All these limitations might have resulted in misclassification of some strokes as cryptogenic and
GJLP–CNRI/Science Photo Library
Ischaemic stroke of undetermined cause
Published Online July 28, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00149-0 See Articles page 903
871
used for the first time in ALS in a study investigating lithium carbonate,9 in response to a report describing the potential benefits with lithium that triggered a frenzy of hope in the ALS community. The use of historical controls was well justified in the case of lithium because various randomised controlled trials with lithium were already on the horizon. Yet nearly everyone agrees that studies with historical controls are useful only for probing of possibilities, and that any possible efficacy shown should be followed by appropriate randomised controlled trials. Because the ALS community has already accumulated a large amount of data, meaningful historical control-based studies might become a viable option in the future,10 but how to select historical controls in each trial is still an issue of fundamental importance. Although the DiPALS investigators fully discuss possible reasons for poor outcomes with non-invasive ventilation and diaphragm pacing in their report,8 the mechanisms of why this happened could have been investigated with use of periodical nocturnal pulse oximetry and, in selected patients, polysomnograms could have been obtained. This information would have helped us learn how to manage non-invasive ventilation in the future. Our experience with diaphragm pacing raises several important questions of how to undertake ALS clinical trials properly and from early stages. There is a strong need for new international guidelines for clinical trials of ALS, which would detail how to undertake more effective and efficient clinical trials in the future, especially because the current guidelines are already 16 years old.11
Hiroshi Mitsumoto Eleanor and Lou Gehrig MDA/ALS Center, Department of Neurology, Columbia University Medical Center, New York, NY 10032 USA [email protected] I declare no competing interests. Copyright © Mitsumoto et al. Open Access article distributed under the terms of CC BY. 1
2
3
4
5
6
7 8
9
10
11
Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009; 73: 1227–33. Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol 2012; 19: 360–75. Atkeson AD, RoyChoudhury A, Harrington-Moroney G, Shah B, Mitsumoto H, Basner RC. Patient-ventilator asynchrony with nocturnal noninvasive ventilation in ALS. Neurology 2011; 77: 549–55. Onders RP, DiMarco AF, Ignagni AR, Mortimer JT. The learning curve for investigational surgery—lessons learned from laparoscopic diaphragm pacing for chronic ventilator dependence. Surg Endosc 2005; 19: 633–37. Lechtzin N, Scott Y, Busse AM, Clawson LL, Kimball R, Wiener CM. Early use of non-invasive ventilation prolongs survival in subjects with ALS. Amyotroph Lateral Scler 2007; 8: 185–88. US Food and Drug Administration. Summary of safety and probably benefit (SSPB). 2011. http://www.accessdata.fda.gov/cdrh_docs/pdf10/ H100006b.pdf (accessed June 30, 2015). Fitzgerald S. Is a diaphragm pacing system for ALS ready for prime time? Neurology Today 2011; 11: 44–45. DiPALS Writing Committee, on behalf of the DiPALS Study Group Collaborators. Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. Lancet Neurol 2015; published online July 31. http://dx.doi.org/10.1016/S14744422(15)00152-0. Miller RG, Moore DH, Forshew DA, et al. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 2011; 77: 973–79. Küffner R, Zach N, Norel R, et al. Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression. Nat Biotechnol 2015; 33: 51–57. Miller RG, Munsat TL, Swash M, Brooks BR. Consensus guidelines for the design and implementation of clinical trials in ALS. World Federation of Neurology committee on Research. J Neurol Sci 1999; 169: 2–12.
Constraint-induced movement therapy translated into practice Constraint-induced movement therapy (CIMT) is the massed task practice of the affected limb with shaping techniques and constraint of the unaffected limb. CIMT and modified CIMT are the most empirically supported approaches to rehabilitation of the upper limbs after stroke. CIMT is a successful example1 of translating findings from basic research (from animal studies),2 to human clinical research (including phase 1–3 clinical trials)3,4 and practicewww.thelancet.com/neurology Vol 14 September 2015
based research (phase 3 randomised trials).5–7 In one study5 of 222 patients with stroke-related upper limb dysfunction, the effect of CIMT given before or after routine therapy was compared with standard care; however, without data from clinical practice, the assessment of CIMT or modified CIMT is arguably a conceptual investigation that will not benefit patients who receive regular therapy at clinics. In The Lancet Neurology, Anne Barzel and colleagues7 now report
Published Online July 29, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00183-0 See Articles page 893
869
Comment
their endeavours to validate the use of modified CIMT for neurorehabilitation in clinical practice. In a cluster-randomised controlled trial of homebased modified CIMT (home CIMT), 156 patients with upper-limb dysfunction after stroke were randomly assigned to receive 4 weeks of either home CIMT or standard therapy. Both groups of patients had 5 h of contact with a professional therapist but patients in the home CIMT group practiced exercises together with a non-professional coach (eg, a caregiver) in addition to the professional contact. Patients in the control group did not practice with a coach, and mandatory practice was not required beyond professional therapy time. The primary outcomes were self-perceived quality of movement, assessed by the Motor Activity Log (MALQOM), and objective performance time, assessed by the Wolf Motor Function Test (WMFT-PT). After 4 weeks of intervention, the self-perceived functional use of the affected limb had improved more in patients in the home CIMT group than in patients in the control group (MAL-QOM betweengroup difference in change from baseline 0·26, 95% CI 0·05–0·46; p=0·0156).7 Patients in the home CIMT group did additional hours of exercise wearing a resting glove to immobilise the non-affected hand, whereas patients in the control group did not report these data and possibly did not have as many extra hours of exercise or practice. Although home CIMT was found to improve the selfperceived use of the stroke-affected arm in daily life, the assessor-reported primary outcome measure was not improved by home CIMT (WMFT-PT between-group difference in change from baseline 2·65%, –17·94 to 28·40; p=0·8152). The secondary objective measures showed little clinically significant difference. Because the effects of home CIMT were limited to the selfreported outcomes, efforts towards augmenting the effectiveness of home CIMT on objective health-related outcomes are necessary in future studies. Anne Barzel and colleagues7 have translated CIMT into clinical practice for ambulatory care, and have adapted CIMT for use as a home-based programme with the intention of reducing use of resources by professionals and patients. However, this study was biased with respect to treatment dose, which is common for studies of CIMT, in that patients in the home CIMT group received hours of exercise and immobilising the 870
non-affected hand at home in addition to professional therapy whereas patients in the control group received therapy only during therapy contact either at home or at a practice. Future randomised controlled trials powered with a large number of patients who are representative of the general post-stroke population and a control group matched for dose and treatment location in regular routine practice will be essential to validate the effects of home-based modified CIMT.4 The patients in the home CIMT group relied on a nonprofessional coach to supervise their practice, limiting the applicability of this home protocol. The coach might not be able to recognise the patient’s compensatory strategies or impaired skills during task practice and provide immediate feedback, which might weaken the improvement of the patients receiving home CIMT. Telerehabilitation strategies allowing therapists to monitor or coach patient home-practice remotely might be a plausible way to implement home-based CIMT.8 Additionally, the cost-effectiveness of homebased modified CIMT in any form needs to be estimated and compared with that of conventional therapy. Bilateral priming, which involves bimanual, repetitive, and mirror-symmetric movement training, is an emerging strategy to accelerate motor recovery and promote functional improvements after stroke. Bilateral priming is suggested to enhance rebalancing of corticomotor excitability and is efficacious in augmenting upper limb recovery when done before upper limb therapy.9 To augment the treatment effects of modified CIMT, future research could investigate how the sequential combination of bilateral priming with modified CIMT affects stroke recovery. An important criterion for receiving CIMT or modified CIMT is the ability to extend one or more fingers of the affected limb, suggesting that these therapy forms are restricted to patients with a mild to moderate paresis of the limb. Portable and affordable upper-limb robotics could be integrated into CIMT or modified CIMT10 and implemented at home to enhance hand function during daily tasks in patients with severe movement deficits. Anne Barzel and colleagues have made an important contribution by adapting modified CIMT for stroke rehabilitation into clinical practice, and their findings should provide a basis for future stroke research. The issues regarding a control group that is matched by www.thelancet.com/neurology Vol 14 September 2015
Comment
dose and location, augmentation of treatment effects, expansion of applicability, and cost-effectiveness should be addressed in future research.
2 3
4
*Ching-Yi Wu, Ku-Chou Chang Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, College of Medicine, Chang Gung University, and Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan 333 (C-Y Wu); Division of Cerebrovascular Diseases, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, and Department of Senior Citizen Service Management, Yuh-Ing Junior College, Kaohsiung, Taiwan (K-C Chang) [email protected] C-YW and K-CC contributed equally to this Comment. C-YW and K-CC have received grants from the Ministry of Science and Technology, Chang Gung Memorial Hospital, and Healthy Aging Research Center at Chang Gung University. C-YW has also received grant from the National Health Research Institutes in Taiwan. 1
Westfall JM, Mold J, Fagnan L. Practice-based research—“blue highways” on the NIH roadmap. JAMA 2007; 297: 403–06.
5
6 7
8
9
10
Knapp HD, Taub E, Berman AJ. Movements in monkeys with deafferented forelimbs. Exp Neurol 1963; 7: 305–15. Koyama T, Sano K, Tanaka S, Hatanaka T, Domen K. Effective targets for constraint induced movement therapy for patients with upper-extremity impairment after stroke. NeuroRehabilitation 2007; 22: 287–93. Lin K, Wu C, Liu J, Chen Y, Hsu C. Constraint-induced therapy versus dose-matched control intervention to improve motor ability, basic/extended daily functions, and quality of life in stroke. Neurorehabil Neural Repair 2009; 23: 160–65. Wolf S, Winstein C, Miller J, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 2006; 296: 2095–104. Kwakkel G, Veerbeek JM, van Wegen EEH, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol 2015; 14: 224–34. Barzel A, Ketels G, Stark A, et al. Home-based constraint-induced movement therapy for patients with upper limb dysfunction after stroke (HOMECIMT): a cluster-randomised, controlled trial. Lancet Neurol 2015; published online July 29. http://dx.doi.org/10.1016/S1474-4422(15)00147-7. Brennan DM, Lum PS, Uswatte G, Taub E, Gilmore BM, Barman J. A telerehabilitation platform for home-based automated therapy of arm function. Conf Proc IEEE Eng Med Biol Soc 2011; 2011: 1819–22. Stinear CM, Barber PA, Petoe MA, Anwar S, Byblow WD. Bilateral priming accelerates recovery of upper limb function after stroke: a randomized controlled trial. Stroke 2014; 45: 205–10. Page SJ, Hill V, White S. Portable upper extremity robotics is as efficacious as upper extremity rehabilitative therapy: a randomized controlled pilot trial. Clin Rehabil 2013; 27: 494–50.
The definition of cryptogenic stroke or stroke of undetermined origin is affected by the current knowledge of the cause and pathogenesis of stroke and by the availability, comprehensiveness, quality, and timeliness of the ancillary investigations undertaken to discover the cause of the stroke.1 In The Lancet Neurology, Linxin Li and colleagues2 report findings from a population-based study of the burden, outcome, risk factors, and long-term prognosis of cryptogenic stroke in patients with a first transient ischaemic attack (TIA) or ischaemic stroke. They found that of 2555 first ischaemic events, 812 (32%) were cryptogenic. The study shows that the prognosis of cryptogenic stroke and the risk of recurrence are similar to those of large artery disease and small vessel disease. For example, death or dependency at 6 months was similar after cryptogenic stroke compared with large artery and small vessel subtypes combined (23% vs 27%; p=0·26), as was the 10-year risk of recurrence (32% vs 27%; p=0·91). Secondary stroke prevention must be similarly aggressive and appropriate in stroke with and without identified cause. The findings from this Article question the role of paroxysmal atrial fibrillation as the major cause of cryptogenic stroke, which contrasts with the present enthusiasm for the use of technology to detect www.thelancet.com/neurology Vol 14 September 2015
paroxysmal atrial fibrillation3 and for the possibility to prevent recurrent cryptogenic stroke with anticoagulants. The results of this study are especially important for health-care policy makers, because they show the burden of cryptogenic stroke, the rationale for a comprehensive investigation into the cause of every ischaemic stroke, and the need to provide stroke centres with access to the necessary ancillary diagnostic procedures. The diagnostic work up used in this study is unfortunately still not routinely used for every patient with ischaemic stroke, neither in the UK nor in mainland Europe. In developing countries, such diagnostic instruments are a distant mirage. This study has some limitations that hamper the translation of its results into routine practice: both TIAs and strokes were included, and the diagnosis of TIA can be erroneous even when done by a specialist; the causative investigation was incomplete, especially in phase 1; the search for paroxysmal atrial fibrillation was not pursued intensively; the investigation of the cause of stroke in recurrent strokes was incomplete; and the newest devices for prolonged heart rhythm monitoring were not used. All these limitations might have resulted in misclassification of some strokes as cryptogenic and
GJLP–CNRI/Science Photo Library
Ischaemic stroke of undetermined cause
Published Online July 28, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00149-0 See Articles page 903
871