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Kawasaki Y, Kawagoe K, Chen CJ, Teruya K, Sakasegawa Y, Doh-ura K. Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner. J Virol 2007; 81: 12889–98. Trevitt CR, Collinge J. A systematic review of prion therapeutics in experimental models. Brain 2006; 129: 2241–65. Forloni G, Iussich S, Awan T, et al. Tetracyclines affect prion infectivity. Proc Natl Acad Sci USA 2002; 99: 10849–54. Doh-ura K, Ishikawa K, Murakami-Kubo I, et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol 2004; 78: 4999–5006. Moreno JA, Halliday M, Molloy C, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013; 5: 206ra138. Bone I, Belton L, Walker AS, Darbyshire J. Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. Eur J Neurol 2008; 15: 458–64. Tsuboi Y, Doh-Ura K, Yamada T. Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases. Neuropathology 2009; 29: 632–36.
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Honda H, Sasaki K, Minaki H, et al. Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion. Neuropathology 2012; 32: 124–32. De Luigi A, Colombo L, Diomede L, et al. The efficacy of tetracyclines in peripheral and intracerebral prion infection. PLoS One 2008; 3: e1888. Berry DB, Lu D, Geva M, et al. Drug resistance confounding prion therapeutics. Proc Natl Acad Sci U S A 2013; 110: E4160–69. Lu D, Giles K, Li Z, et al. Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice. J Pharmacol Exp Ther 2013; 347: 325–38. Johnson DY, Dunkelberger DL, Henry M, et al. Sporadic Jakob-Creutzfeldt disease presenting as primary progressive aphasia. JAMA Neurol 2013; 70: 254–57. Rabinovici GD, Wang PN, Levin J, et al. First symptom in sporadic Creutzfeldt-Jakob disease. Neurology 2006; 66: 286–87. Mead S, Ranopa M, Gopalakrishnan GS, et al. PRION-1 scales analysis supports use of functional outcome measures in prion disease. Neurology 2011; 77: 1674–83. Prusiner SB. Cell biology. A unifying role for prions in neurodegenerative diseases. Science 2012; 336: 1511–13.
Effects of robotic therapy of the arm after stroke Published Online December 30, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70285-0 See Articles page 159
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The development of robots to help with rehabilitation of paretic arms and legs after stroke is based on translational research. The exoskeleton robot ARMin has seven actuated axes (ie, degrees of freedom), making it the most advanced commercially available robot offering antigravity support for a paretic arm. The efficient gears and sensors in the exoskeleton control the position and interaction force between robot and user, allowing patients with severe impairment to safely practise daily tasks and play games in a virtual environment. In The Lancet Neurology, Verena Klamroth-Marganska and colleagues report findings from their multicentre, parallel-group randomised trial of the ARMin robot in patients with moderate-to-severe arm paresis after a stroke and who had had motor impairment for more than 6 months.1 77 eligible individuals were randomly assigned to receive 24 sessions (each lasting at least 45 min) of either robotic or conventional therapy. Patients assigned to robotic therapy had significantly greater increases in score on the arm section of the FuglMeyer assessment (FMA-UE) than did those assigned to conventional therapy (mean difference in score 0·78 points, 95% CI 0·03–1·53; p=0·041).1 Additionally, robotic therapy was shown to be safe. The investigators do acknowledge that the difference between the groups was small, which could well be a result of the minor flaws that are inherent in rehabilitation trials, such as increased enthusiasm for novel therapies in unmasked patients and therapists. Indeed, similar numbers
of patients in both groups achieved the clinically meaningful change in FMA-UE score: 13 (34%) of the 38 patients assigned to robotic therapy and nine (26%) of the 35 assigned to conventional therapy included in analyses improved by at least 5 points.1 The results of this well done Swiss trial agree with the available evidence: training with an arm robot is safe2–4 and improves body functions, activities, and participation (ie, social functioning) equally as well as the same amount of conventional therapy offered by a therapist.2,4 Klamroth-Marganska and colleagues’ findings1 support previous findings suggesting that intensity of practice is associated with improvement in function, and that this important principle also applies to robotic therapy after stroke.2,3,5 Additionally, robots do not get tired, can generate more repetitions than can a therapist in the same time, offer accurate feedback about patients’ performance, and can be fun to use. As would be expected, Klamroth-Marganska and colleagues’ proof-of-concept trial1 raises several questions for bioengineers and clinicians who design and test rehabilitation robots. First, little is known about what patients actually learn when showing improvement in motor performance after stroke. Longitudinal studies with intensive, repeated threedimensional kinematics6,7 have shown that patients learn to adapt to, or compensate for, their motor deficits by using their trunk and affected arm muscles differently. However, the synergy-dependent intra-limb couplings (ie, functionally related, stereotyped patterns of muscle www.thelancet.com/neurology Vol 13 February 2014
Comment
contractions) that prevent normal movement with a paretic arm do not change after 3 months after stroke.6,7 There is little evidence that patients can increase the number of degrees of freedom in intra-limb coordination after the first 3 months, as reflected by FMA-UE scores.6,8 Therefore, future trials in patients with chronic impairment after stroke should have a primary outcome measure that includes improvements of arm function by compensation strategies. Depending on prognosis for arm recovery,9 future assist-as-needed robots and their training protocols should allow compensation with the trunk and synergy-dependent adaptation strategies of the paretic arm during meaningful tasks.6,7 Additionally, robot treatment protocols should be more transparent about patient-in-charge or robot-in-charge modes of training after stroke. Decisions about how motor control should be assisted by robot-assisted therapy should be based on fundamental knowledge about motor recovery and the use of compensatory strategies in daily activities during the different phases after stroke.2,6,7 Second, the antigravity support for shoulder abduction provided by the ARMin robot can effectively reduce synergy-dependent coupling between the shoulder and elbow of the paretic arm. Therefore, arm robots with antigravity support can maximise joint excursion of the elbow and shoulder, and reaching with the paretic arm.10 However, the generalisability of this artificial training to real-world tasks needs to be investigated further. In line with other trials,2,3 the antigravity support could have prevented strength increase in the paretic arm muscles, whereas strengthening a paretic arm has been shown to be an effective therapy after stroke.11 This finding suggests that future arm robot programmes with antigravity support should combine task-dependent training with strengthening programmes, or include adjustment for antigravity support in a more assist-asneeded way during training sessions.
Finally, the ARMin robot is the most advanced commercially available arm robot, but is also the most expensive. Future studies should investigate whether ARMin can be used to reduce health-care costs. Broadband telematics can be used to monitor patients’ performances at home and to collect data remotely during robot-induced exercise programmes.2,4 However, the cost-effectiveness assessment of home-based robots is still in its infancy. *Gert Kwakkel, Carel G M Meskers Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam, Vrije Universiteit Medical Center, 1007 MB, Amsterdam, Netherlands (GK, CGMM) [email protected] We declare that we have no conflicts of interest. 1
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Klamroth-Marganska V, Blanco J, Campen K, et al. Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial. Lancet Neurol 2013; published online Dec 30. http://dx.doi.org/10.1016/S1474-4422(13)70305-3. Kwakkel G, Kollen BJ, Krebs HI. Effects of robot-assisted therapy on upper limb recovery after stroke: a systematic review. Neurorehabil Neural Repair 2008; 22: 111–21. Mehrholz J, Hädrich A, Platz T, Kugler J, Pohl M. Electromechanical and robot-assisted arm training for improving generic activities of daily living, arm function, and arm muscle strength after stroke. Cochrane Database Syst Rev 2012; 6: CD006876. Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med 2010; 362: 1772–83. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet 2011; 377: 1693–702. Van Kordelaar J, Van Wegen EE, Nijland RH, Daffertshofer A, Kwakkel G. Understanding adaptive motor control of the paretic upper limb early poststroke: the EXPLICIT-stroke program. Neurorehabil Neural Repair 2013; 27: 854–63. Buma F, Kwakkel G, Ramsey N. Understanding upper limb recovery after stroke. Restor Neurol Neurosci 2013; 31: 707–22. Duncan PW, Goldstein LB, Horner RD, Landsman PB, Samsa GP, Matchar DB. Similar motor recovery of upper and lower extremities after stroke. Stroke 1994; 25: 1181–88. Kwakkel G, Kollen BJ. Predicting activities after stroke: what is clinically relevant? Int J Stroke 2013; 8: 25–32. Ellis MD, Sukal-Moulton T, Dewald JP. Progressive shoulder abduction loading is a crucial element of arm rehabilitation in chronic stroke. Neurorehabil Neural Repair 2009; 23: 862–69. Harris JE, Eng JJ. Strength training improves upper-limb function in individuals with stroke: a meta-analysis. Stroke 2010; 41: 136–40.
NMDAR encephalitis: which specimens, and the value of values The detection of neural-reactive IgG autoantibodies in serum and CSF aids the diagnosis of autoimmune neurological disorders.1 In a paraneoplastic context, these biomarkers also direct the search for occult neoplasia. For the assessment of autoimmune encephalitis, sensitivity for clinically pertinent www.thelancet.com/neurology Vol 13 February 2014
autoantibodies is highest when both serum and CSF are tested, but some individual IgG autoantibodies are more readily detected in one specimen type.2 Assay methods also influence sensitivity and specificity, and a broad repertoire of techniques is required to assess patients comprehensively.3–5
Published Online December 18, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70277-1 See Articles page 167
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Kawasaki Y, Kawagoe K, Chen CJ, Teruya K, Sakasegawa Y, Doh-ura K. Orally administered amyloidophilic compound is effective in prolonging the incubation periods of animals cerebrally infected with prion diseases in a prion strain-dependent manner. J Virol 2007; 81: 12889–98. Trevitt CR, Collinge J. A systematic review of prion therapeutics in experimental models. Brain 2006; 129: 2241–65. Forloni G, Iussich S, Awan T, et al. Tetracyclines affect prion infectivity. Proc Natl Acad Sci USA 2002; 99: 10849–54. Doh-ura K, Ishikawa K, Murakami-Kubo I, et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol 2004; 78: 4999–5006. Moreno JA, Halliday M, Molloy C, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013; 5: 206ra138. Bone I, Belton L, Walker AS, Darbyshire J. Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK. Eur J Neurol 2008; 15: 458–64. Tsuboi Y, Doh-Ura K, Yamada T. Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases. Neuropathology 2009; 29: 632–36.
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Honda H, Sasaki K, Minaki H, et al. Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion. Neuropathology 2012; 32: 124–32. De Luigi A, Colombo L, Diomede L, et al. The efficacy of tetracyclines in peripheral and intracerebral prion infection. PLoS One 2008; 3: e1888. Berry DB, Lu D, Geva M, et al. Drug resistance confounding prion therapeutics. Proc Natl Acad Sci U S A 2013; 110: E4160–69. Lu D, Giles K, Li Z, et al. Biaryl amides and hydrazones as therapeutics for prion disease in transgenic mice. J Pharmacol Exp Ther 2013; 347: 325–38. Johnson DY, Dunkelberger DL, Henry M, et al. Sporadic Jakob-Creutzfeldt disease presenting as primary progressive aphasia. JAMA Neurol 2013; 70: 254–57. Rabinovici GD, Wang PN, Levin J, et al. First symptom in sporadic Creutzfeldt-Jakob disease. Neurology 2006; 66: 286–87. Mead S, Ranopa M, Gopalakrishnan GS, et al. PRION-1 scales analysis supports use of functional outcome measures in prion disease. Neurology 2011; 77: 1674–83. Prusiner SB. Cell biology. A unifying role for prions in neurodegenerative diseases. Science 2012; 336: 1511–13.
Effects of robotic therapy of the arm after stroke Published Online December 30, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70285-0 See Articles page 159
132
The development of robots to help with rehabilitation of paretic arms and legs after stroke is based on translational research. The exoskeleton robot ARMin has seven actuated axes (ie, degrees of freedom), making it the most advanced commercially available robot offering antigravity support for a paretic arm. The efficient gears and sensors in the exoskeleton control the position and interaction force between robot and user, allowing patients with severe impairment to safely practise daily tasks and play games in a virtual environment. In The Lancet Neurology, Verena Klamroth-Marganska and colleagues report findings from their multicentre, parallel-group randomised trial of the ARMin robot in patients with moderate-to-severe arm paresis after a stroke and who had had motor impairment for more than 6 months.1 77 eligible individuals were randomly assigned to receive 24 sessions (each lasting at least 45 min) of either robotic or conventional therapy. Patients assigned to robotic therapy had significantly greater increases in score on the arm section of the FuglMeyer assessment (FMA-UE) than did those assigned to conventional therapy (mean difference in score 0·78 points, 95% CI 0·03–1·53; p=0·041).1 Additionally, robotic therapy was shown to be safe. The investigators do acknowledge that the difference between the groups was small, which could well be a result of the minor flaws that are inherent in rehabilitation trials, such as increased enthusiasm for novel therapies in unmasked patients and therapists. Indeed, similar numbers
of patients in both groups achieved the clinically meaningful change in FMA-UE score: 13 (34%) of the 38 patients assigned to robotic therapy and nine (26%) of the 35 assigned to conventional therapy included in analyses improved by at least 5 points.1 The results of this well done Swiss trial agree with the available evidence: training with an arm robot is safe2–4 and improves body functions, activities, and participation (ie, social functioning) equally as well as the same amount of conventional therapy offered by a therapist.2,4 Klamroth-Marganska and colleagues’ findings1 support previous findings suggesting that intensity of practice is associated with improvement in function, and that this important principle also applies to robotic therapy after stroke.2,3,5 Additionally, robots do not get tired, can generate more repetitions than can a therapist in the same time, offer accurate feedback about patients’ performance, and can be fun to use. As would be expected, Klamroth-Marganska and colleagues’ proof-of-concept trial1 raises several questions for bioengineers and clinicians who design and test rehabilitation robots. First, little is known about what patients actually learn when showing improvement in motor performance after stroke. Longitudinal studies with intensive, repeated threedimensional kinematics6,7 have shown that patients learn to adapt to, or compensate for, their motor deficits by using their trunk and affected arm muscles differently. However, the synergy-dependent intra-limb couplings (ie, functionally related, stereotyped patterns of muscle www.thelancet.com/neurology Vol 13 February 2014
Comment
contractions) that prevent normal movement with a paretic arm do not change after 3 months after stroke.6,7 There is little evidence that patients can increase the number of degrees of freedom in intra-limb coordination after the first 3 months, as reflected by FMA-UE scores.6,8 Therefore, future trials in patients with chronic impairment after stroke should have a primary outcome measure that includes improvements of arm function by compensation strategies. Depending on prognosis for arm recovery,9 future assist-as-needed robots and their training protocols should allow compensation with the trunk and synergy-dependent adaptation strategies of the paretic arm during meaningful tasks.6,7 Additionally, robot treatment protocols should be more transparent about patient-in-charge or robot-in-charge modes of training after stroke. Decisions about how motor control should be assisted by robot-assisted therapy should be based on fundamental knowledge about motor recovery and the use of compensatory strategies in daily activities during the different phases after stroke.2,6,7 Second, the antigravity support for shoulder abduction provided by the ARMin robot can effectively reduce synergy-dependent coupling between the shoulder and elbow of the paretic arm. Therefore, arm robots with antigravity support can maximise joint excursion of the elbow and shoulder, and reaching with the paretic arm.10 However, the generalisability of this artificial training to real-world tasks needs to be investigated further. In line with other trials,2,3 the antigravity support could have prevented strength increase in the paretic arm muscles, whereas strengthening a paretic arm has been shown to be an effective therapy after stroke.11 This finding suggests that future arm robot programmes with antigravity support should combine task-dependent training with strengthening programmes, or include adjustment for antigravity support in a more assist-asneeded way during training sessions.
Finally, the ARMin robot is the most advanced commercially available arm robot, but is also the most expensive. Future studies should investigate whether ARMin can be used to reduce health-care costs. Broadband telematics can be used to monitor patients’ performances at home and to collect data remotely during robot-induced exercise programmes.2,4 However, the cost-effectiveness assessment of home-based robots is still in its infancy. *Gert Kwakkel, Carel G M Meskers Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam, Vrije Universiteit Medical Center, 1007 MB, Amsterdam, Netherlands (GK, CGMM) [email protected] We declare that we have no conflicts of interest. 1
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Klamroth-Marganska V, Blanco J, Campen K, et al. Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial. Lancet Neurol 2013; published online Dec 30. http://dx.doi.org/10.1016/S1474-4422(13)70305-3. Kwakkel G, Kollen BJ, Krebs HI. Effects of robot-assisted therapy on upper limb recovery after stroke: a systematic review. Neurorehabil Neural Repair 2008; 22: 111–21. Mehrholz J, Hädrich A, Platz T, Kugler J, Pohl M. Electromechanical and robot-assisted arm training for improving generic activities of daily living, arm function, and arm muscle strength after stroke. Cochrane Database Syst Rev 2012; 6: CD006876. Lo AC, Guarino PD, Richards LG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med 2010; 362: 1772–83. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet 2011; 377: 1693–702. Van Kordelaar J, Van Wegen EE, Nijland RH, Daffertshofer A, Kwakkel G. Understanding adaptive motor control of the paretic upper limb early poststroke: the EXPLICIT-stroke program. Neurorehabil Neural Repair 2013; 27: 854–63. Buma F, Kwakkel G, Ramsey N. Understanding upper limb recovery after stroke. Restor Neurol Neurosci 2013; 31: 707–22. Duncan PW, Goldstein LB, Horner RD, Landsman PB, Samsa GP, Matchar DB. Similar motor recovery of upper and lower extremities after stroke. Stroke 1994; 25: 1181–88. Kwakkel G, Kollen BJ. Predicting activities after stroke: what is clinically relevant? Int J Stroke 2013; 8: 25–32. Ellis MD, Sukal-Moulton T, Dewald JP. Progressive shoulder abduction loading is a crucial element of arm rehabilitation in chronic stroke. Neurorehabil Neural Repair 2009; 23: 862–69. Harris JE, Eng JJ. Strength training improves upper-limb function in individuals with stroke: a meta-analysis. Stroke 2010; 41: 136–40.
NMDAR encephalitis: which specimens, and the value of values The detection of neural-reactive IgG autoantibodies in serum and CSF aids the diagnosis of autoimmune neurological disorders.1 In a paraneoplastic context, these biomarkers also direct the search for occult neoplasia. For the assessment of autoimmune encephalitis, sensitivity for clinically pertinent www.thelancet.com/neurology Vol 13 February 2014
autoantibodies is highest when both serum and CSF are tested, but some individual IgG autoantibodies are more readily detected in one specimen type.2 Assay methods also influence sensitivity and specificity, and a broad repertoire of techniques is required to assess patients comprehensively.3–5
Published Online December 18, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70277-1 See Articles page 167
133
