- Email: [email protected]
Botulinum toxin A for upper limb spasticity
Comment
International efforts to improve trial design for rare diseases have been made. Statistical considerations (frequentist vs Bayesian approaches) and the search for biomarkers are certainly important. Markers that allow tracking of disease progression and change in response to treatment are needed. Imaging markers that have shown short-term effect sizes of greater than 1 in similar disorders should be used.12 Change in individual slopes of markers or clinical parameters could be calculated in run-in trials and multimodal integration of biomarkers could be used to detect changes over time. The next step is to determine exactly which subgroups of patients with cerebellar ataxia respond to riluzole and could therefore benefit from treatment.
2
3
4
5
6
7
8 9
10
Alexandra Durr APHP, Department of Genetics, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, University Hospital Pitié-Salpêtrière, Paris, France [email protected]
11 12
Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 2011; 77: 1035–41. Tezenas du Montcel S, Charles P, Goizet C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol 2012; 69: 500–08. Marelli C, Figoni J, Charles P, et al. Annual change in Friedreich’s ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord 2012; 27: 135–38. Chan E, Charles P, Ribai P, et al. Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. Mov Disord 2011; 26: 534–38. Schmitz-Hübsch T, Tezenas du Montcel S, Baliko L, et al. Reliability and validity of the International Cooperative Ataxia Rating Scale: a study in 156 spinocerebellar ataxia patients. Mov Disord 2006; 21: 699–704. Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; 12: 650–58. Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The preclinical stage of spinocerebellar ataxias. Neurology 2015; 85: 96–103. Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014; 51: 479–86. Monin ML, Tezenas du Montcel S, Marelli C, et al. Survival and severity in dominant cerebellar ataxias. Ann Clin Transl Neurol 2015; 2: 202–07. Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol 2012; 197: 167–77. Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational data to inform clinical trial design in Huntington’s disease. J Neurol Neurosurg Psychiatry 2015; published online Feb 10. DOI:10.1136/jnnp-2014-309768.
I declare no competing interests. 1
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebocontrolled trial. Lancet Neurol 2015; published online Aug 26. http://dx.doi.org/10.1016/S1474-4422(15)00201-X.
Upper limb spasticity is a common neurological impairment resulting from an upper neuron syndrome after stroke or traumatic brain injury. Although well distinguishable clinically, spasticity is still poorly understood. This lack of understanding interferes with research to establish the effects of botulinum toxin A injections, which is further hampered by differences in dosing regimens, injection sites, concurrent treatments, outcomes selected, timing of assessments, and poor methodological quality of insufficiently powered, placebo-controlled trials.1 In The Lancet Neurology, Jean-Michel Gracies and colleagues2 show in a double-blind, placebo-controlled, trial that 500 U or 1000 U of abobotulinumtoxinA injected in the most spastic muscle groups around the elbow, wrist, or finger flexors is safe and significantly reduces muscle tone compared with placebo. They found mean reductions of –0·9 (18%) and –1·1 (22%) www.thelancet.com/neurology Vol 14 October 2015
of 5 points maximally in the primary outcome, the modified Ashworth Scale (MAS), for 500 U and 1000 U, respectively, compared with placebo at 4 weeks after injection. The beneficial effects of abobotulinumtoxinA were sustained at 12 weeks. Despite significant positive ratings given by clinicians using the Physician Global Assessment scale, patients reported no significant differences on the Disability Assessment Scale (DAS), 36-Item Short Form Health Survey (SF-36), or EuroQol (EQ-5D). Gracies and colleagues deserve praise for their major achievement in doing a properly powered placebocontrolled trial involving 34 different rehabilitation or neurology clinics in nine different countries. Their findings are consistent with those of the largest powered trial in the specialty—BoTULS (n=333),3 suggesting that botulinum toxin A injections are able to reduce muscle tone temporarily, although evidence for
Thomas Fredberg/Science Photo Library
Botulinum toxin A for upper limb spasticity
Published Online August 27, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00222-7 See Articles page 992
969
Comment
favourable effects on perceived disability or upper limb capacity is still lacking. In addition to the high dropout rate beyond 12 weeks because of the many patients who needed another botulinum toxin A injection, the current study has some shortcomings that are almost inherent to the complexity of doing a large pragmatic multicentre trial on a still poorly understood problem. First, one might question whether the MAS, as a measure of observerperceived resistance to passive manipulation at the joint level, is a proper primary outcome in trials of botulinum toxin A.4,5 Not only are there concerns about its reliability and responsiveness to change,6 but also the MAS is seen as a poor surrogate marker for spasticity, measuring it indirectly.4–7 In particular, the biomechanical changes in muscles and soft tissues—such as changed properties of the muscle contractile elements, decreased number of sarcomeres with increased sarcomere length, and altered soft tissue properties resulting in changed elasticity and viscocity8—contribute to velocity-dependent resistance to stretching. Most importantly, the MAS measures the increased joint resistance passively, which bears little resemblance to active functional conditions.4–7 In view of this complexity, it is not surprising that a treatment to counteract the hyperexcitability component of spasticity does not automatically result in improved upper limb function.2 Unfortunately, the study did not assess clinically important task-specific improvements in the upper limb, such as reaching and grasping performance. Also, there is increasing evidence that the effects of botulinum toxin A injections can be maximised by a team of health professionals such as nurses, physical and occupational therapists, and orthotists,9 who collectively aim to improve upper limb capacity, improve basic upper limb activities such as hand hygiene and dressing ability,3 or reduce deformity and pain after stroke or traumatic brain injury.1 The current study raises several questions needing to be addressed through further research. First, can we reach consensus on definitions for key problems like spasticity, muscle tone, contractures, and joint resistance? Second, can we distinguish between the different components of spasticity and their effects on increased joint resistance? Mechanical devices10 and haptic robots4,5 have become available to standardise measurement conditions and help discriminate between the neuronal and biomechanical components 970
of spasticity, and the effects of botulinum toxin A on this association. More fundamentally, studies are needed to establish how changes in the neuronal component of spasticity interact longitudinally with the progressive biomechanical changes in different phenotypes after stroke or traumatic brain injury. Trials are needed in which the accompanying biomechanical changes, including muscle shortening and contractures, are prevented with botulinum toxin A injections at an early stage after brain injury. Third, the assumed association between reducing muscle tone and meaningful gains in task performance of the upper paretic limb is still poorly understood and seldom adequately investigated. Biomechanical and neurophysiological measurements, preferably done during meaningful tasks, are needed to investigate this association.4,5 The selection of muscles for botulinum toxin A injections11 and the use of guidance techniques such as ultrasound also need further investigation.12 Last, botulinum toxin A is an expensive treatment that warrants cost-effectiveness analyses alongside large pragmatic trials.3 Overall, the study by Gracies and colleagues2 shows that an injection of abotulinumtoxinA is safe to apply and results in significantly reduced muscle tone for up to 3 months after stroke or traumatic brain injury. However, whether botulinum toxin A injections are useful for improving upper limb capacity remains unsolved. *Gert Kwakkel, Carel G M Meskers Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam, Vrije Universiteit Medical Center, 1007 MB, Amsterdam, Netherlands (GK, CGMM); and Amsterdam Rehabilitation Research Centre Reade Amsterdam, Netherlands (GK) [email protected] We declare no competing interests. 1
2
3
4
Foley N, Pereira S, Salter K, Fernandez MM, Speechley M, Sequeira K, Miller T, Teasell R. Treatment with botulinum toxin improves upperextremity function post stroke: a systematic review and meta-analysis. Arch Phys Med Rehabil 2013; 94: 977–89. Gracies J-M, Brashear A, Jech R, et al, for the International AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group. Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol 2015; published online Aug 27. http://dx.doi. org/10.1016/S1474-4422(15)00216-1. Shaw L, Rodgers H, Price C, et al; BoTULS investigators. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A. Health Technol Assess 2010; 14: 1–113. Fleuren JF, Voerman GE, Erren-Wolters CV, et al. Stop using the Ashworth Scale for the assessment of spasticity. J Neurol Neurosurg Psychiatry 2010; 81: 46–52.
www.thelancet.com/neurology Vol 14 October 2015
Comment
5
6
7 8 9
de Vlugt E, de Groot JH, Schenkeveld KE, et al. The relation between neuromechanical parameters and Ashworth score in stroke patients. J Neuroeng Rehabil 2010; 7: 35. Pandyan AD, Johnson GR, Price CIM, et al. A review of the properties and limitations of the Ashworth and Modified Ashworth Scales as measures of spasticity. Clin Rehabil 1999; 13: 373–83. Dietz V, Sinkjaer T. Spastic movement disorder: impaired reflex function and altered muscle mechanics. Lancet Neurol 2007; 6: 725–33. Lieber RL, Steinman S, Barash IA, Chambers H. Structural and functional changes in spastic skeletal muscle. Muscle Nerve 2004; 29: 615–27. Demetrios M, Khan F, Turner-Stokes L, Brand C, McSweeney S. Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity. Cochrane Database Syst Rev 2013; 6: CD009689.
10
11
12
Gäverth J, Eliasson AC, Kullander K, Borg J, Lindberg PG, Forssberg H. Sensitivity of the NeuroFlexor method to measure change in spasticity after treatment with botulinum toxin A in wrist and finger muscles. J Rehabil Med 2014; 46: 629–34. Baguley IJ, Nott MT, Turner-Stokes L, et al. Investigating muscle selection for botulinum toxin-A injections in adults with post-stroke upper limb spasticity. J Rehabil Med 2011; 43: 1032–37. Grigoriu AI, Dinomais M, Rémy-Néris O, Brochard S. Impact of injectionguiding techniques on the effectiveness of botulinum toxin for the treatment of focal spasticity and dystonia: a systematic review. Arch Phys Med Rehabil 2015; published online May 14. DOI:10.1016/j. apmr.2015.05.002.
A diagnostic algorithm for Parkinson’s disease: what next?
www.thelancet.com/neurology Vol 14 October 2015
exception of REM sleep behaviour disorder, these non-motor symptoms are relatively common in the general population and are individually non-specific for Parkinson’s disease. Symptom constellations, however, can provide enhanced specificity. For example, in a study of a large prospective cohort, Ross and colleagues10 noted that Parkinson’s disease incidence was only modestly increased in men with any one prodromal symptom at baseline, while those with two symptoms had a 10 times increase in incidence of subsequent Parkinson’s disease. Nalls and colleagues investigated whether an algorithm based on constellations of non-motor features in combination with several Parkinson’s disease-associated risk factors could correctly
Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00192-1 See Articles page 1002
PR Michel Zanca/ISM/Science Photo Library
The pathological processes that cause Parkinson’s disease begin years or even decades before the presentation of the defining motor features. Diagnosis is typically made at Braak stage IV, when Lewy pathology has ascended from the olfactory bulb and lower brainstem to involve the substantia nigra.1 By this time, at least 50% of pigmented dopaminergic neurons are either dead or dying.2 Thus, diseasemodifying interventions are likely to fail if initiated after the onset of typical motor features. This problem has prompted much research into the characterisation of risk factors and clinical features associated with early, prodromal Parkinson’s disease. In their study in The Lancet Neurology, Mike Nalls and colleagues develop and test an algorithm that aims to distinguish study participants with prevalent Parkinson’s disease from healthy controls, without relying on their motor features.3 The authors’ hope is that if such an algorithm were applied to the general population, it might help to identify people who are likely to have prodromal Parkinson’s disease, although a crosssectional study design cannot confirm this hypothesis. The main finding of the study is a confirmation of a well known observation: most people with Parkinson’s disease have impaired olfaction, and most neurologically normal controls do not. Symptoms attributable to pathological changes in the lower brainstem and peripheral nervous system in early Parkinson’s disease include impaired olfaction, constipation, disturbed sleep (eg, REM sleep behaviour disorder, daytime sleepiness), visual changes, autonomic dysfunction, and pain.4–9 Although ubiquitous in Parkinson’s disease, with the
Dopamine transporter imaging (DAT scan) in a healthy control (top) and a patient with Parkinson’s disease (bottom)
971
International efforts to improve trial design for rare diseases have been made. Statistical considerations (frequentist vs Bayesian approaches) and the search for biomarkers are certainly important. Markers that allow tracking of disease progression and change in response to treatment are needed. Imaging markers that have shown short-term effect sizes of greater than 1 in similar disorders should be used.12 Change in individual slopes of markers or clinical parameters could be calculated in run-in trials and multimodal integration of biomarkers could be used to detect changes over time. The next step is to determine exactly which subgroups of patients with cerebellar ataxia respond to riluzole and could therefore benefit from treatment.
2
3
4
5
6
7
8 9
10
Alexandra Durr APHP, Department of Genetics, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, University Hospital Pitié-Salpêtrière, Paris, France [email protected]
11 12
Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 2011; 77: 1035–41. Tezenas du Montcel S, Charles P, Goizet C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol 2012; 69: 500–08. Marelli C, Figoni J, Charles P, et al. Annual change in Friedreich’s ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord 2012; 27: 135–38. Chan E, Charles P, Ribai P, et al. Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. Mov Disord 2011; 26: 534–38. Schmitz-Hübsch T, Tezenas du Montcel S, Baliko L, et al. Reliability and validity of the International Cooperative Ataxia Rating Scale: a study in 156 spinocerebellar ataxia patients. Mov Disord 2006; 21: 699–704. Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; 12: 650–58. Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The preclinical stage of spinocerebellar ataxias. Neurology 2015; 85: 96–103. Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014; 51: 479–86. Monin ML, Tezenas du Montcel S, Marelli C, et al. Survival and severity in dominant cerebellar ataxias. Ann Clin Transl Neurol 2015; 2: 202–07. Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol 2012; 197: 167–77. Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational data to inform clinical trial design in Huntington’s disease. J Neurol Neurosurg Psychiatry 2015; published online Feb 10. DOI:10.1136/jnnp-2014-309768.
I declare no competing interests. 1
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebocontrolled trial. Lancet Neurol 2015; published online Aug 26. http://dx.doi.org/10.1016/S1474-4422(15)00201-X.
Upper limb spasticity is a common neurological impairment resulting from an upper neuron syndrome after stroke or traumatic brain injury. Although well distinguishable clinically, spasticity is still poorly understood. This lack of understanding interferes with research to establish the effects of botulinum toxin A injections, which is further hampered by differences in dosing regimens, injection sites, concurrent treatments, outcomes selected, timing of assessments, and poor methodological quality of insufficiently powered, placebo-controlled trials.1 In The Lancet Neurology, Jean-Michel Gracies and colleagues2 show in a double-blind, placebo-controlled, trial that 500 U or 1000 U of abobotulinumtoxinA injected in the most spastic muscle groups around the elbow, wrist, or finger flexors is safe and significantly reduces muscle tone compared with placebo. They found mean reductions of –0·9 (18%) and –1·1 (22%) www.thelancet.com/neurology Vol 14 October 2015
of 5 points maximally in the primary outcome, the modified Ashworth Scale (MAS), for 500 U and 1000 U, respectively, compared with placebo at 4 weeks after injection. The beneficial effects of abobotulinumtoxinA were sustained at 12 weeks. Despite significant positive ratings given by clinicians using the Physician Global Assessment scale, patients reported no significant differences on the Disability Assessment Scale (DAS), 36-Item Short Form Health Survey (SF-36), or EuroQol (EQ-5D). Gracies and colleagues deserve praise for their major achievement in doing a properly powered placebocontrolled trial involving 34 different rehabilitation or neurology clinics in nine different countries. Their findings are consistent with those of the largest powered trial in the specialty—BoTULS (n=333),3 suggesting that botulinum toxin A injections are able to reduce muscle tone temporarily, although evidence for
Thomas Fredberg/Science Photo Library
Botulinum toxin A for upper limb spasticity
Published Online August 27, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00222-7 See Articles page 992
969
Comment
favourable effects on perceived disability or upper limb capacity is still lacking. In addition to the high dropout rate beyond 12 weeks because of the many patients who needed another botulinum toxin A injection, the current study has some shortcomings that are almost inherent to the complexity of doing a large pragmatic multicentre trial on a still poorly understood problem. First, one might question whether the MAS, as a measure of observerperceived resistance to passive manipulation at the joint level, is a proper primary outcome in trials of botulinum toxin A.4,5 Not only are there concerns about its reliability and responsiveness to change,6 but also the MAS is seen as a poor surrogate marker for spasticity, measuring it indirectly.4–7 In particular, the biomechanical changes in muscles and soft tissues—such as changed properties of the muscle contractile elements, decreased number of sarcomeres with increased sarcomere length, and altered soft tissue properties resulting in changed elasticity and viscocity8—contribute to velocity-dependent resistance to stretching. Most importantly, the MAS measures the increased joint resistance passively, which bears little resemblance to active functional conditions.4–7 In view of this complexity, it is not surprising that a treatment to counteract the hyperexcitability component of spasticity does not automatically result in improved upper limb function.2 Unfortunately, the study did not assess clinically important task-specific improvements in the upper limb, such as reaching and grasping performance. Also, there is increasing evidence that the effects of botulinum toxin A injections can be maximised by a team of health professionals such as nurses, physical and occupational therapists, and orthotists,9 who collectively aim to improve upper limb capacity, improve basic upper limb activities such as hand hygiene and dressing ability,3 or reduce deformity and pain after stroke or traumatic brain injury.1 The current study raises several questions needing to be addressed through further research. First, can we reach consensus on definitions for key problems like spasticity, muscle tone, contractures, and joint resistance? Second, can we distinguish between the different components of spasticity and their effects on increased joint resistance? Mechanical devices10 and haptic robots4,5 have become available to standardise measurement conditions and help discriminate between the neuronal and biomechanical components 970
of spasticity, and the effects of botulinum toxin A on this association. More fundamentally, studies are needed to establish how changes in the neuronal component of spasticity interact longitudinally with the progressive biomechanical changes in different phenotypes after stroke or traumatic brain injury. Trials are needed in which the accompanying biomechanical changes, including muscle shortening and contractures, are prevented with botulinum toxin A injections at an early stage after brain injury. Third, the assumed association between reducing muscle tone and meaningful gains in task performance of the upper paretic limb is still poorly understood and seldom adequately investigated. Biomechanical and neurophysiological measurements, preferably done during meaningful tasks, are needed to investigate this association.4,5 The selection of muscles for botulinum toxin A injections11 and the use of guidance techniques such as ultrasound also need further investigation.12 Last, botulinum toxin A is an expensive treatment that warrants cost-effectiveness analyses alongside large pragmatic trials.3 Overall, the study by Gracies and colleagues2 shows that an injection of abotulinumtoxinA is safe to apply and results in significantly reduced muscle tone for up to 3 months after stroke or traumatic brain injury. However, whether botulinum toxin A injections are useful for improving upper limb capacity remains unsolved. *Gert Kwakkel, Carel G M Meskers Department of Rehabilitation Medicine, MOVE Research Institute Amsterdam, Vrije Universiteit Medical Center, 1007 MB, Amsterdam, Netherlands (GK, CGMM); and Amsterdam Rehabilitation Research Centre Reade Amsterdam, Netherlands (GK) [email protected] We declare no competing interests. 1
2
3
4
Foley N, Pereira S, Salter K, Fernandez MM, Speechley M, Sequeira K, Miller T, Teasell R. Treatment with botulinum toxin improves upperextremity function post stroke: a systematic review and meta-analysis. Arch Phys Med Rehabil 2013; 94: 977–89. Gracies J-M, Brashear A, Jech R, et al, for the International AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group. Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol 2015; published online Aug 27. http://dx.doi. org/10.1016/S1474-4422(15)00216-1. Shaw L, Rodgers H, Price C, et al; BoTULS investigators. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A. Health Technol Assess 2010; 14: 1–113. Fleuren JF, Voerman GE, Erren-Wolters CV, et al. Stop using the Ashworth Scale for the assessment of spasticity. J Neurol Neurosurg Psychiatry 2010; 81: 46–52.
www.thelancet.com/neurology Vol 14 October 2015
Comment
5
6
7 8 9
de Vlugt E, de Groot JH, Schenkeveld KE, et al. The relation between neuromechanical parameters and Ashworth score in stroke patients. J Neuroeng Rehabil 2010; 7: 35. Pandyan AD, Johnson GR, Price CIM, et al. A review of the properties and limitations of the Ashworth and Modified Ashworth Scales as measures of spasticity. Clin Rehabil 1999; 13: 373–83. Dietz V, Sinkjaer T. Spastic movement disorder: impaired reflex function and altered muscle mechanics. Lancet Neurol 2007; 6: 725–33. Lieber RL, Steinman S, Barash IA, Chambers H. Structural and functional changes in spastic skeletal muscle. Muscle Nerve 2004; 29: 615–27. Demetrios M, Khan F, Turner-Stokes L, Brand C, McSweeney S. Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity. Cochrane Database Syst Rev 2013; 6: CD009689.
10
11
12
Gäverth J, Eliasson AC, Kullander K, Borg J, Lindberg PG, Forssberg H. Sensitivity of the NeuroFlexor method to measure change in spasticity after treatment with botulinum toxin A in wrist and finger muscles. J Rehabil Med 2014; 46: 629–34. Baguley IJ, Nott MT, Turner-Stokes L, et al. Investigating muscle selection for botulinum toxin-A injections in adults with post-stroke upper limb spasticity. J Rehabil Med 2011; 43: 1032–37. Grigoriu AI, Dinomais M, Rémy-Néris O, Brochard S. Impact of injectionguiding techniques on the effectiveness of botulinum toxin for the treatment of focal spasticity and dystonia: a systematic review. Arch Phys Med Rehabil 2015; published online May 14. DOI:10.1016/j. apmr.2015.05.002.
A diagnostic algorithm for Parkinson’s disease: what next?
www.thelancet.com/neurology Vol 14 October 2015
exception of REM sleep behaviour disorder, these non-motor symptoms are relatively common in the general population and are individually non-specific for Parkinson’s disease. Symptom constellations, however, can provide enhanced specificity. For example, in a study of a large prospective cohort, Ross and colleagues10 noted that Parkinson’s disease incidence was only modestly increased in men with any one prodromal symptom at baseline, while those with two symptoms had a 10 times increase in incidence of subsequent Parkinson’s disease. Nalls and colleagues investigated whether an algorithm based on constellations of non-motor features in combination with several Parkinson’s disease-associated risk factors could correctly
Published Online August 11, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00192-1 See Articles page 1002
PR Michel Zanca/ISM/Science Photo Library
The pathological processes that cause Parkinson’s disease begin years or even decades before the presentation of the defining motor features. Diagnosis is typically made at Braak stage IV, when Lewy pathology has ascended from the olfactory bulb and lower brainstem to involve the substantia nigra.1 By this time, at least 50% of pigmented dopaminergic neurons are either dead or dying.2 Thus, diseasemodifying interventions are likely to fail if initiated after the onset of typical motor features. This problem has prompted much research into the characterisation of risk factors and clinical features associated with early, prodromal Parkinson’s disease. In their study in The Lancet Neurology, Mike Nalls and colleagues develop and test an algorithm that aims to distinguish study participants with prevalent Parkinson’s disease from healthy controls, without relying on their motor features.3 The authors’ hope is that if such an algorithm were applied to the general population, it might help to identify people who are likely to have prodromal Parkinson’s disease, although a crosssectional study design cannot confirm this hypothesis. The main finding of the study is a confirmation of a well known observation: most people with Parkinson’s disease have impaired olfaction, and most neurologically normal controls do not. Symptoms attributable to pathological changes in the lower brainstem and peripheral nervous system in early Parkinson’s disease include impaired olfaction, constipation, disturbed sleep (eg, REM sleep behaviour disorder, daytime sleepiness), visual changes, autonomic dysfunction, and pain.4–9 Although ubiquitous in Parkinson’s disease, with the
Dopamine transporter imaging (DAT scan) in a healthy control (top) and a patient with Parkinson’s disease (bottom)
971