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Dystonia in complex regional pain syndrome type I.

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ANNALS
of Neurology
The DNA samples were from the Human Genetic Bank of
Patients Affected by Parkinson Disease and Parkinsonisms
of the Parkinson Institute, Instituti Clinici di Perfezionamento, Italy (http://www.parkinson.it/dnabank.htm). This
biobank is supported by the Italian Telethon Foundation
(grant GTB07001) and by the Fondazione Grigioni per il
Morbo di Parkinson.
1
Dipartimento di Biologia e Genetica per le Scienze Mediche,
Università degli Studi di Milano, and 2Parkinson Institute,
Clinical Institute of Improvement, Milan, Italy
References
1.
Elstner M, Morris C, Heim K et al. Single cell expression profiling
of dopaminergic neurons combined with association analysis
identifies pyridoxal kinase as Parkinson’s disease gene. Ann Neurol 2009;66:792–798.
2.
Taylor C. Mutation scanning using high-resolution melting. Biochem Soc Trans 2009;37:433– 437.
3.
Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet 2005;366:1315–1323.
DOI: 10.1002/ana.21964
Reply
Matthias Elstner, MD,1,2 Peter Lichtner, PhD,1
Claudia Schulte, MD,3 Thomas Gasser, MD,3
Thomas Meitinger, MD,1,4 Holger Prokisch, PhD,1,4 and
Douglass M. Turnbull, MD, PhD5
We recently used array-based expression profiling to identify differentially regulated genes in laser-captured substantia nigra neurons of 8 Parkinson disease (PD) patients and 9 controls. We
subsequently tested for genetic association of candidate genes in
idiopathic PD. Association analysis was limited to genes surviving Bonferroni correction for multiple testing, although several
known PD-associated genes were also differentially regulated.
We found an association of rs2010795 in the pyridoxal kinase
(PDXK) gene in German PD cases versus population-based controls, and replicated this association in 2 further case-control
samples from the United Kingdom and Italy.1
In an attempt to replicate the association with the PDXK
locus, Vilariño-Güell et al and Guella et al tested rs2010795 in
7 different case control samples from various populations and
found no association. In contrast, a recently published genomewide association study (GWAS) shows significant p values for
this PDXK single nucleotide polymorphism (SNP).2 In this
study, separate analysis of the US samples (971 PD patients and
3,034 controls) also reveals a signal. A joint analysis of the German studies,1,2 the United States,2 and the dataset provided by
Vilariño-Güell et al and Guella et al (a total of 5420 cases,
8,570 controls) generates a p value of 3.6E-05 (Fig).
As the effect size of the reported polymorphism is small,
the sample sizes of studies performed so far are underpowered.
In addition, genome-wide SNP marker sets have to be used to
exclude a gross genetic substructure, as was done in the GWAS
412
FIGURE: Forest plot of meta-analysis of single nucleotide
polymorphism rs2010795 in Caucasian case-control studies:
1 ⴝ Elstner et al,1 2 ⴝ Vilariño-Güell et al, 3 ⴝ Guella et
al, 4 ⴝ Simón-Sánchez.2 Joint analysis is shown for fixed
and random effect models. a ⴝ Combined analysis of
1,062 German cases and 942 German controls.1,2 b ⴝ Data
calculated based on the genome-wide association study
dataset.2 OR ⴝ odds ratio; CI ⴝ confidence interval;
MAF%: minor allel frequency (Parkinson disease/controls
[PD/C]). p-values are shown when significant.
controls.1,2 Meta-analysis of large datasets, as reported for traits
such as obesity or diabetes, must be awaited to resolve the issue.3
1
Institute of Human Genetics, Helmholtz Center Munich,
German Research Center for Environmental Health,
Neuherberg, Germany, 2Department of Neurology, Ludwig
Maximilian University, Munich, Germany, 4Institute of
Human Genetics, Technical University Munich, Munich,
Germany, and 3Hertie Institute for Clinical Brain Research,
Section for Neurodegenerative Diseases, University of
Tübingen, Tübingen, Germany, 5Institute of Ageing and
Health, Mitochondrial Research Group, Newcastle University,
Newcastle upon Tyne, United Kingdom
References
1.
Elstner M, Morris C, Heim K, et al. Single cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson’s disease gene. Ann
Neurol 2009;66:792–798.
2.
Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease.
Nat Genet 2009;41:1308 –1312.
3.
O’Rahilly S. Human genetics illuminates the paths to metabolic
disease. Nature 2009;462:307–314.
DOI: 10.1002/ana.21967
Dystonia in Complex Regional Pain Syndrome
Type I
Anthony E. Lang, MD, FRCPC,1,2
and Robert Chen, MB, BChir, MSc, FRCPC1,2
We were interested to read Oaklander and Fields’s1 Neurological Progress article dealing with complex regional pain syndrome
type I (CRPSI). We would like to limit our comments to the
Volume 67, No. 3
movement disorders, primarily dystonia, seen in these patients.
As the authors point out, many movement disorders specialists
have emphasized the similarities between so-called CRSP/dystonia and psychogenic dystonia, and this remains a source of regular debate at international meetings, most recently a Movement
Disorder Society–sponsored symposium on psychogenic movement disorders held this year in Washington, DC. Indeed, the
senior author has been a part of this debate related to a patient
that she reported as experiencing development of CRPS I as a
consequence of varicose vein stripping.2 Movement disorders experts who reviewed the published videotape of this patient
pointed out that the concomitant tremor in her opposite limb,
which had typical clinical features of a psychogenic tremor, provided support for the argument that her CRPS/dystonia could
also have been psychogenic.3,4
Much of the discussion in Oaklander and Fields’s1 article
relates to the postulated critical contribution of damage to small
fibers in causing the syndrome. However, as the authors acknowledge, dystonia is not a feature of other, better characterized, small-fiber neuropathies. Thus, they invoke the potential
concomitant involvement of large-fiber damage to account for
dystonia. Throughout the article, the authors emphasize the important similarities between CRPS I (no obvious nerve injury)
and CRPS II (where nerve injury is clearly evident). If the
pathogenic mechanisms underlying many of the overlapping
symptoms in the two disorders are the same and dystonia relates
to large fiber damage, one would expect that dystonia would
occur more frequently in CRPS II than in CRPS I. However,
not only is this not the case, but dystonia and other movement
disorders are either rarely5 or never6 seen in patients with CRPS
II, a feature that has been used to strongly support arguments
favoring a psychogenic basis for these movement disorders in
CRPS I.6,7 Concomitant large-fiber damage causing dystonia is
also difficult to reconcile with the striking responses described in
these patients to intrathecal baclofen infusion8 (we have argued
elsewhere that this could be explained by a placebo response9).
The authors describe a variety of extremely interesting possible
pathogenetic mechanisms for various clinical features of CRPS I.
However, presumably these would evolve over time as a consequence of the small-fiber damage. This contrasts with the common experience that the dystonia occurs quite suddenly and
quickly after rather minor injury; this historical feature is an
extremely common characteristic of psychogenic movement disorders in general.7 The authors mention the stereotyped flexion
of ulnar-innervated digits in the hand, but nothing in the invoked pathogenetic mechanisms explain this unusual pattern of
dystonia, which interestingly, spares pincer grip. The authors
discuss potential mechanisms for spread of CRPS symptoms including “mirror” spread. Even accepting these mechanisms, it is
difficult to explain patterns of spread reported in many CRPS/
dystonia cases; in one report, 3 of 10 patients had spread not to
the ipsilateral limb or the mirror contralateral limb but to the
contralateral diagonal limb.10
Finally, the authors cite Schrag and colleagues’11 study
emphasizing that, in 103 patients with fixed limb dystonia, 20%
of whom fulfilled criteria for CRPS, 45% were found to have no
March, 2010
evidence of a psychogenic cause. However, they failed to point
out that only 41 of these 103 patients were assessed prospectively, whereas 26 were evaluated intensively using structured
neuropsychiatric assessments. Strikingly, in this latter group, 12
of the 14 patients with features of CRPS (86%) had evidence
for a psychogenic movement disorder, 3 documented and 9
probable.11
Despite the interesting review of the potential neuroscientific underpinnings of CRPS I, we were surprised that the authors failed to mention contrary opinions regarding the cause of
the disorder, and that there was a complete absence of discussion of the potential role of psychological factors in causing (eg,
predisposing to) or maintaining the problem and no discussion
of the importance of addressing these factors in managing these
difficult cases. Although we would not claim that all patients
with CRPS/dystonia have a psychogenic movement disorder,
this has been the case in a large proportion of them that we have
seen, and psychological factors play an important role in many
others. This does not deny an important role for poorly understood central nervous system mechanisms underlying the development and maintenance of the symptoms including central
neuroplasticity. Ignoring the potential role of true “psychosomatic” factors and concentrating exclusively on the physiological
consequences of small-fiber damage fails to deal with the patient
in the holistic fashion that is necessary to find more effective
treatments for this extremely disabling condition.
1
Department of Medicine, University of Toronto, and
Division of Neurology, Toronto Western Hospital, Toronto,
Ontario, Canada
2
References
1.
Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/
complex regional pain syndrome type I a small-fiber neuropathy?
Ann Neurol 2009;65:629 – 638.
2.
Oaklander AL. Progression of dystonia in complex regional pain
syndrome. Neurology 2004;63:751.
3.
Reich SG, Weiner WJ. Progression of dystonia in complex regional pain syndrome. Neurology 2005;64:2162–2163; author reply 2162–2163.
4.
Morgan JC, Sethi K, Lang AE. Progression of dystonia in complex regional pain syndrome. Neurology 2005;64:2162–2163.
5.
Birklein F, Riedl B, Sieweke N, et al. Neurological findings in
complex regional pain syndromes—analysis of 145 cases. Acta
Neurol Scand 2000;101:262–269.
6.
Verdugo RJ, Ochoa JL. Abnormal movements in complex regional pain syndrome: assessment of their nature. Muscle Nerve
2000;23:198 –205.
7.
Sa DS, Galvez-Jimenez N, Lang AE. Psychogenic movement disorders. In: Watts RL, Koller WC, eds. Movement disorders: neurologic principles and practice. New York: McGraw Hill, 2004:
891–914.
8.
Van Hilten BJ, Van de Beek WJT, Hoff JI, et al. Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med 2000;343:625– 630.
9.
Lang AE, Angel M, Bhatia K, et al. Myoclonus in complex regional pain syndrome. Mov Disord 2009;24:314 –316.
413
ANNALS
of Neurology
10.
Van Hilten JJ, Van de Beek WJT, Vein AA, et al. Clinical aspects
of multifocal or generalized tonic dystonia in reflex sympathetic
dystrophy. Neurology 2001;56:1762–1765.
11.
Schrag A, Trimble M, Quinn N, Bhatia K. The syndrome of fixed
dystonia: an evaluation of 103 patients. Brain 2004;127:
2360 –2372.
1
Prince of Wales Medical Research Institute, 2Faculty of
Medicine, University of New South Wales, Sydney, Australia,
3
Academic Department of Physiotherapy and Wolfson Centre
for Age Related Diseases, King’s College London, London,
United Kingdom, and 4Department of Clinical and Cognitive
Neuroscience, University of Heidelberg, Heidelburg, Germany
DOI: 10.1002/ana.21830
References
Enhancing the Neurologist’s Role in Complex
Regional Pain Syndrome
G. Lorimer Moseley, PhD,1,2 Michael Thacker, PhD,3
and Herta Flor, PhD4
We applaud Oaklander and Fields’ comprehensive review1 of
the literature concerning the role of small-fiber neuropathy in
complex regional pain syndrome (CRPS). The review builds on
a body of elegant work by Oaklander’s group and others, and
presents a compelling argument that many clinical features of
CRPS are consistent with persistent dysfunction of C and A␦
fibers. The review culminates in treatment recommendations,
and states that rehabilitation and physical therapy are critical.
Unfortunately, what constitutes “rehabilitation” or “physical
therapy” is not considered. This is like stating that medications
are critical but not considering which ones. Oaklander and
Fields1 are by no means the first to make this oversight; guidelines the world over recommend “physical therapy” or “rehabilitation” for CRPS but make no attempt to sort the wheat from
the chaff. This issue is of utmost importance because many and
varied treatments for CRPS are undertaken under the banner of
“rehabilitation,” but most of them are probably not helpful. It is
not that empirical data do not exist (see Daly and Bialocerkowski2 for review); for example, several randomized, controlled trials show that graded motor imagery reduces pain and
disability in chronic CRPS.2 The number needed to treat for a
50% decrease in pain and a 4-point decline on a 10-point scale
of disability is about 4,3 which compares favorably with any
other treatment for chronic CRPS, including spinal cord stimulators, for which Oaklander and Fields1 state there is documented efficacy and they are indicated for CRPS. Oaklander
and Fields1 go on to note the absence of data for pharmacological treatment of CRPS and turn to the results of randomized,
controlled trials for other neuralgias. Randomized, controlled
trials also show that cognitive-behavioral programs reduce pain
and disability in other neuralgias (see Turk4 for review), and
that sensory discrimination training reduces pain in chronic
phantom limb pain.5 Sensory discrimination training has already
been extended to patients with chronic CRPS, where preliminary data appear supportive.6 Oaklander and Fields1 compiled a
rigorous and discerning review of the role of small-fiber pathology in CRPS, which provided a strong basis for their proposal
that neurologists should return to a central role in CRPS care.
We humbly suggest that this role would be greatly enhanced,
and most importantly, patient outcomes would be improved, if
the same rigor and discernment were applied to evaluating
evidence-based treatment options that fall under the broad category of “rehabilitation.”
414
1.
Oaklander AL, Fields HL. Is reflex sympathetic dystrophy/
complex regional pain syndrome type I a small-fiber neuropathy?
Ann Neurol 2009;65:629 – 638.
2.
Daly A, Bialocerkowski A. Does evidence support physiotherapy
management of adult complex regional pain syndrome type
one? A systematic review. Eur J Pain 2009;13:339 –353.
3.
Moseley GL. Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology 2006;67:2129 –2134.
4.
Turk DC. Clinical effectiveness and cost-effectiveness of treatments for patients with chronic pain. Clin J Pain 2002;18:
355–365.
5.
Flor H, Denke C, Schaefer M, Grusser S. Effect of sensory discrimination training on cortical reorganisation and phantom limb
pain. Lancet 2001;357:1763–1764.
6.
Moseley GL, Zalucki NM, Wiech K. Tactile discrimination, but not
tactile stimulation alone, reduces chronic limb pain. Pain 2008;
137:600 – 608.
DOI: 10.1002/ana.21829
Reply to: SNCA Variants Are Associated With
Increased Risk of Multiple System Atrophy
Owen A. Ross, PhD,1 Carles Vilariño-Güell, PhD,1
Zbigniew K. Wszolek, MD,2 Matthew J. Farrer, PhD,1
and Dennis W. Dickson, MD1
Parkinson disease (PD) and multiple system atrophy (MSA) are
disorders distinguished by pathologic accumulation of
␣-synuclein in neurons and glia. A common variation in the
gene for ␣-synuclein (SNCA) is known to be associated with
PD, but its role in MSA is unclear. Recently, Scholz et al reported a single-nucleotide polymorphism (SNP) (rs111931074)
in the 3⬘ region of SNCA , originally identified in a genomewide association study in PD, that increased the risk for MSA
by nearly 6-fold in a subset of pathologically confirmed cases.1
Our studies assessing the influence of SNCA variation in PD
have examined the frequency of this SNP in a PD patientcontrol series from Ireland, Serbia, and Germany.2,3 Although
significant association was observed across the SNCA locus,
rs111931074 was not associated with increased risk of PD, with
a very low frequency (⬍1%) of minor allele homozygotes found
in both patients and controls.
The association observed by Scholz et al of SNCA
rs111931074 with MSA was most pronounced under a recessive
model, especially in pathologically confirmed MSA. A frequency
of the TT minor allele homozygote was 2% in a clinical series
(n ⫽ 308) and 6% in a pathological series (n ⫽ 92) of MSA
patients, compared with 0.6% in controls (n ⫽ 3,889). The
effect of this variant appears to be most pronounced in pathologically confirmed MSA, with a dilution of the signal in clinical
samples. The high diagnostic error in MSA may be the reason
Volume 67, No. 3
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