Comment
International eorts 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 eect 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 benet
from treatment.
Alexandra Durr
APHP, Department of Genetics, Inserm U 1127, CNRS UMR 7225,
Sorbonne Universits, UPMC Univ Paris 06 UMR S 1127,
Institut du Cerveau et de la Moelle pinire, ICM,
University Hospital Piti-Salptrire, Paris, France
alexandra.durr@upmc.fr
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, placebo-
controlled trial. Lancet Neurol 2015; published online Aug 26.
http://dx.doi.org/10.1016/S1474-4422(15)00201-X.
Botulinum toxin A for upper limb spasticity
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 eects of botulinum toxin A
injections, which is further hampered by dierences in
dosing regimens, injection sites, concurrent treatments,
outcomes selected, timing of assessments, and poor
methodological quality of insuciently 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 nger exors is safe and signicantly
reduces muscle tone compared with placebo. They
found mean reductions of 09 (18%) and 11 (22%)
www.thelancet.com/neurology Vol 14 October 2015
2 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: 103541.
3 Tezenas du Montcel S, Charles P, Goizet C, et al. Factors inuencing
disease progression in autosomal dominant cerebellar ataxia and spastic
paraplegia. Arch Neurol 2012; 69: 50008.
4 Marelli C, Figoni J, Charles P, et al. Annual change in Friedreichs ataxia
evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is
independent of disease severity. Mov Disord 2012; 27: 13538.
5 Chan E, Charles P, Ribai P, et al. Quantitative assessment of the evolution
of cerebellar signs in spinocerebellar ataxias. Mov Disord 2011;
26: 53438.
6 Schmitz-Hbsch 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: 699704.
7 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: 65058.
8 Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The
preclinical stage of spinocerebellar ataxias. Neurology 2015; 85: 96103.
9 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: 47986.
10 Monin ML, Tezenas du Montcel S, Marelli C, et al. Survival and severity in
dominant cerebellar ataxias. Ann Clin Transl Neurol 2015; 2: 20207.
11 Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol 2012;
197: 16777.
12 Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational
data to inform clinical trial design in Huntingtons disease.
J Neurol Neurosurg Psychiatry 2015; published online Feb 10.
DOI:10.1136/jnnp-2014-309768.
of 5 points maximally in the primary outcome, the
modied Ashworth Scale (MAS), for 500 U and 1000 U,
respectively, compared with placebo at 4 weeks after
injection. The benecial eects of abobotulinumtoxinA
Thomas Fredberg/Science Photo Library
were sustained at 12 weeks. Despite signicant positive
ratings given by clinicians using the Physician Global
Assessment scale, patients reported no signicant
dierences 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 Published Online
August 27, 2015
achievement in doing a properly powered placebo- http://dx.doi.org/10.1016/
controlled trial involving 34 dierent rehabilitation S1474-4422(15)00222-7
or neurology clinics in nine dierent countries. Their See Articles page 992
ndings are consistent with those of the largest
powered trial in the specialtyBoTULS (n=333),3
suggesting that botulinum toxin A injections are able to
reduce muscle tone temporarily, although evidence for
969
 Comment
favourable eects 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 observer-
perceived 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.47 In particular, the biomechanical changes in
muscles and soft tissuessuch 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
viscocity8contribute to velocity-dependent resistance
to stretching. Most importantly, the MAS measures the
increased joint resistance passively, which bears little
resemblance to active functional conditions.47 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-specic improvements
in the upper limb, such as reaching and grasping
performance. Also, there is increasing evidence that
the eects 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 denitions for key problems
like spasticity, muscle tone, contractures, and joint
resistance? Second, can we distinguish between the
dierent components of spasticity and their eects 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 eects 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 dierent 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-eectiveness
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 signicantly 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)
g.kwakkel@vumc.nl
We declare no competing interests.
1 Foley N, Pereira S, Salter K, Fernandez MM, Speechley M, Sequeira K,
Miller T, Teasell R. Treatment with botulinum toxin improves upper-
extremity function post stroke: a systematic review and meta-analysis.
Arch Phys Med Rehabil 2013; 94: 97789.
2 Gracies J-M, Brashear A, Jech R, et al, for the International
AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group. Safety and
ecacy 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.
3 Shaw L, Rodgers H, Price C, et al; BoTULS investigators. BoTULS:
a multicentre randomised controlled trial to evaluate the clinical
eectiveness and cost-eectiveness of treating upper limb spasticity due to
stroke with botulinum toxin type A. Health Technol Assess 2010; 14: 1113.
4 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: 4652.
www.thelancet.com/neurology Vol 14 October 2015

5 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.
6 Pandyan AD, Johnson GR, Price CIM, et al. A review of the properties and
limitations of the Ashworth and Modied Ashworth Scales as measures of
spasticity. Clin Rehabil 1999; 13: 37383.
7 Dietz V, Sinkjaer T. Spastic movement disorder: impaired reex function
and altered muscle mechanics. Lancet Neurol 2007; 6: 72533.
8 Lieber RL, Steinman S, Barash IA, Chambers H. Structural and functional
changes in spastic skeletal muscle. Muscle Nerve 2004; 29: 61527.
9 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.
A diagnostic algorithm for Parkinsons disease: what next?
The pathological processes that cause Parkinsons
disease begin years or even decades before the
presentation of the dening 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, disease-
modifying 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 Parkinsons 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 Parkinsons 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 Parkinsons disease, although a cross-
sectional study design cannot conrm this hypothesis.
The main nding of the study is a conrmation
of a well known observation: most people with
Parkinsons 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 Parkinsons disease include impaired
olfaction, constipation, disturbed sleep (eg, REM
sleep behaviour disorder, daytime sleepiness),
visual changes, autonomic dysfunction, and pain.49
Although ubiquitous in Parkinsons disease, with the
www.thelancet.com/neurology Vol 14 October 2015
Comment
10 Gverth 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 nger muscles.
J Rehabil Med 2014; 46: 62934.
11 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: 103237.
12 Grigoriu AI, Dinomais M, Rmy-Nris O, Brochard S. Impact of injection-
guiding techniques on the eectiveness 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.
exception of REM sleep behaviour disorder, these Published Online
August 11, 2015
non-motor symptoms are relatively common in the http://dx.doi.org/10.1016/
general population and are individually non-specic S1474-4422(15)00192-1
for Parkinsons disease. Symptom constellations, See Articles page 1002
however, can provide enhanced specicity. For
example, in a study of a large prospective cohort,
Ross and colleagues10 noted that Parkinsons 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 Parkinsons disease.
Nalls and colleagues investigated whether an
algorithm based on constellations of non-motor
features in combination with several Parkinsons
disease-associated risk factors could correctly
PR Michel Zanca/ISM/Science Photo Library
Dopamine transporter imaging (DAT scan) in a healthy control (top) and a patient with Parkinsons disease
(bottom)
971