LETTERS: NEW O B S E RVAT I O N S
Acoustic Assessment of Voice and
Speech Disorders in Parkinson’s
Disease Through Quick Vocal Test
The disorders of voice and speech in Parkinson’s disease
(PD) result from involvements in several subsystems includ-
ing respiration, phonation, articulation, and prosody.1–3
We investigated the feasibility of acoustic measures for the
identification of voice and speech disorders in PD, using a
quick vocal test consisting of sustained phonation, diadocho-
kinetic task, and running speech. Various traditional and
novel acoustic measurements have been designed in order to
be gender independent, represent all speech subsystems,
reduce the time required for voice investigation, and provide
a reliable automated assessment in practice.4
Patients and Methods
A total of 46 Czech native participants were recruited.
Twenty-four of them fulfilled the diagnostic criteria for PD
and were examined before the symptomatic treatment was
started: 20 men, 4 women; mean age (6 SD), 60.9 6 11.2
years; duration of PD symptoms, 31.3 6 22.3 months (range,
6–84 months); H&Y stage, 2.2 6 0.5 (range, 1–3); and
UPDRS motor score, 17.4 6 7.1 (range, 5–32); with UPDRS
speech item ¼ 0 in 13 patients and speech item ¼ 1 in 11
patients. As a healthy control (HC) group, 22 persons with no
history of neurological or communication disorders were
included: 15 men, 7 women; mean age, 58.7 6 14.6 years. Age
distribution did not differ significantly between the groups.
Each participant was instructed to perform 3 vocal tasks:
[VT1], sustained phonation at a comfortable pitch and loud-
ness as constant and long as possible, at least 5 seconds on 1
breath; [VT2], diadochokinetic (DDK) task requiring rapid,
steady /pa/-/ta/-/ka/ syllable repetition as constant and long
as possible, repeated at least 5 times on 1 breath; and
[VT3], running speech for approximately 80 seconds. For
reproducibility of data, each task was repeated at least 2
times for every subject.
------------------------------------------------------------
*Correspondence to: Evžen Růžička, Department of Neurology,
Charles University in Prague, First Faculty of Medicine and General
University Hospital in Prague, Katerinska 30, Praha 2, Czech Republic;
eruzi@lf1.cuni.cz
Relevant conflicts of interest/financial disclosures: Nothing to report.
The study was partly supported by the Czech Science Foundation,
project GACR 102/08/H008, Czech Ministry of Health, project NT
11331-6/2010, Grant Agency of the Czech Technical University in
Prague, project SGS 10/180/OHK3/2T/13, and Czech Ministry of
Education, projects MSM 0021620849, MSM 6840770012, and MSM
0021620806.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 11 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23680
The extracted speech parameters were assessed using
measures of phonation [VT1] including jitter, shimmer,
noise-to-harmonics ratio (NHR), and harmonics-to-noise
ratio (HNR)5; respiration [VT2] including sound pressure
level decline (SPLD)4; articulation [VT2] including robust
formant periodicity correlation (RFPC), and spectral distance
change variation (SDCV)4; and prosody [VT3] including
voice fundamental frequency variations (F0 SD).6 Supporting
Information Table 1 details the measurements used.
For every subject, average values (speech performances)
for each acoustic measurement were calculated. Two-sided
Wilcoxon rank-sum and Spearman rank tests were per-
formed to find differences between groups and within-group
correlations. Subsequently, an exhaustive search of all possi-
ble measure combinations was performed, and a predictive
model was built using a kernel support vector machine
(SVM) to find the best combination of measurements to dif-
ferentiate PD from HC subjects. Cross-validation with the
leave-one-out method was used to validate reproducibility of
the SVM classifier.7
Results
In total, 116 vocal recordings were collected and used for
classification. Significant differences between the 2 groups
were found in all 8 measurements. In addition, from all per-
formed correlations, statistically significant relationships
were found between several measures of articulation and
phonation and subscores of bradykinesia and rigidity (Sup-
porting Table 2). The best classification performance of
85.0% 6 6.1% was reached in a combination of 4 measures
that represent all PD-related affected speech subsystems,
including the impaired ability to maintain sound pressure
level (SPLD), increased noise components during phonation
(NHR), lowered accuracy of articulation (RFPC), and
reduced melody of speech (F0 SD); see Figure 1. The maxi-
mal classification accuracy using simple task was 81.3% 6
6.9% for running speech, 75.6% 6 8.3% for sustained pho-
nation, and 71.4% 6 8.3% for DDK task; therefore,
reduced melody in running speech appeared essential in
characterizing the vocal impairment in PD.
Discussion
We have designed a quick 2-minute vocal test and investi-
gated the potential of using acoustic analysis in detecting voice
and speech disorders in PD. The method demonstrated that it
can accurately differentiate PD patients from HCs. This could
be of high clinical relevance as subtle abnormalities such as
reduced melody in running speech were detectable from the
early stage of PD. Admittedly, the study has certain limita-
tions. Although the uneven gender representation of patients
and controls could be offset by gender independence of
designed acoustic measurement methods, our sample size
remains rather small. Should our results be confirmed on a
larger population sample, voice and speech disorders might be
considered as early markers of the disease, and acoustic
Movement Disorders, Vol. 26, No. 10, 2011 1951
L E T T E R S : N E W O B S E R V A T I O N S
FIG. 1. The results of the SVM-based classifier for selected pairs of the measures combination with best classification accuracy. The ‘‘o’’ marks are
for PD, the ‘‘x’’ marks are for HC, and the dark gray curves represent the SVM classification boundaries between both groups.
analysis might serve as a simple screening test in view of the
expected advent of neuroprotective treatment. In a more
modest scope, the use of automated acoustic vocal tests
can ease the clinical monitoring of voice and speech disorders
progression as well as the effects of medication on speech pro-
duction and can serve as feedback in voice treatment.
Jan Rusz, MSc,1,2,3 Roman Čmejla, MSc, PhD,1
Hana Růžičková, MSc,3 Jiřı́ Klempı́ř, MD, PhD,3
Veronika Majerová, MD,3 Jana Picmausová, MD,3
Jan Roth, MD, PhD,3 and Evžen Růžička, MD, DSc3*
1
Czech Technical University in Prague, Faculty of
Electrical Engineering, Department of Circuit
Theory, Prague, Czech Republic; 2Charles
University in Prague, First Faculty of Medicine,
Department of Pathophysiology, Prague, Czech
Republic; and 3Charles University in Prague, First
Faculty of Medicine, Department of Neurology
and Centre of Clinical Neuroscience, Prague,
Czech Republic
References
1. Darley FL, Aronson AE, Brown JR. Differential diagnostic patterns
of dysarthria. J Speech Hear Res 1969;12:246–269.
2. Goberman AM, Coelho C. Acoustic analysis of Parkinsonian
speech I: Speech characteristics and L-dopa therapy. Neurorehab
2002;17:237–246.
3. Skodda S, Schlegel U. Speech rate and rhythm in Parkinson’s dis-
ease. Mov Disord 2008;23:985–992.
4. Rusz J, Cmejla R, Ruzickova H, Ruzicka E. Quantitative acoustic
measurements for characterization of voice and speech disorders in
early untreated Parkinson’s disease. J Acoust Soc Am 2011;129:
350–367.
5. Boersma P, Weenink D. Praat, a system for doing phonetics by
computer. Glot Int 2001;5:341–345.
1952 Movement Disorders, Vol. 26, No. 10, 2011
6. Boril H, Pollak P. Direct time domain fundamental estimation of
speech in noisy conditions. In: EUSIPCO Proceedings, Vienna, Aus-
tria; 2004.
7. Franc V, Hlavac V. Statistical pattern recognition toolbox for Mat-
lab. Prague, Czech Republic: Czech Technical University, Faculty
of Electrical Engineering, Center for Machine Perception; 2004.
Available at http://cmp.felk.cvut.cz/. Accessed January 15, 2011.
THAP1 Mutations Are Infrequent in
Spasmodic Dysphonia
Spasmodic dysphonia (SD, laryngeal dystonia) is a rela-
tively rare focal form of dystonia with an estimated preva-
lence of 1 per 23,500.1 In SD the voice is affected as a result
of involuntary movements of 1 or more muscles of the lar-
ynx during speech.2 Mutations in THAP1 (OMIM 609520)
cause DYT6 dystonia.3 DYT6 dystonia patients typically
have prominent laryngeal and oromandibular involvement,
causing speech difficulties, a rare feature in other familial
dystonia syndromes (e.g. DYT1).4 DYT6 families show an
autosomal dominant mode of inheritance, with reduced pen-
etrance and variable expression of symptoms; more than
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*Correspondence to: Marina A.J. Tijssen, Department of Neurology,
Academic Medical Center, University of Amsterdam, Amsterdam, The
Netherlands; M.A.Tijssen@amc.uva.nl
Relevant conflicts of interest/financial disclosures: Justus L Groen
received an AMC Graduate School Scholarship. Katja Ritz and Marina
A.J. Tijssen received research support from the Prinses Beatrix Fund.
Full financial disclosures and author roles may be found in the online
version of this article.
This study was supported by the Prinses Beatrix Fund.
Published online 29 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23682

Table 1. Characteristics of SD patients included in
THAP1 screening
Number of patients
Female
Mean AaO (SD, range) 45.6 (15.3, 7–87)
Mean AaE (SD) 58.2 (14.0)
Positive family history
Early onset (age < 26 y)
Segmental dystonia
Spread to neck
Spread to oromandibular region
Blepharospasm
Writer’s cramp
All patients are of Dutch ancestry.
a
Half of the familial SD patients had an early age at onset. SD, standard
deviation; AaO, age at onset; AaE, age at examination.
90% of mutation carriers show segmental or generalized
dystonia.3,4 Mutation screening of THAP1 in focal and seg-
mental dystonia patient groups showed a mutation fre-
quency below 1%.5–7 Some focal SD patients (with or
without a positive family history) were found to carry non-
synonymous THAP1 mutations.4,5
Here, we studied the frequency of THAP1 mutations in a
consecutive cohort of focal and segmental SD patients
attending the botulinum toxin treatment outpatient clinic.
The study was approved by the local ethics committees of
participating centers. After giving informed consent,
patients were included in a clinical database, and blood
was drawn.
A total of 109 SD patients of Dutch ancestry were
included in this genetic screening study (Table 1). The 3 cod-
ing exons of THAP1 were sequenced in all patients and 185
controls (Caucasians from the Dutch Blood Bank), including
the 50 untranslated region (UTR) and 500 bp of the 30 UTR
(ABI 3730 capillary system; Applied Biosystems, Carlsbad,
CA). To exclude possible mutations at splice sites, at least
50 base pairs of the upstream and downstream intronic
sequences that flank each exon were sequenced. Sequences
were analyzed using CodonCode software (Dedham, MA;
reference sequence: NM_018105.2) and Alamut 1.5 Interac-
tive Biosoftware (Rouen, France).
Of the 109 screened SD patients, including 89 focal and
20 segmental SD patients, 1 patient (0.9%) carried a hetero-
zygous missense mutation, c.151A>G (p.Ser51Gly), in exon
2 of THAP1. This patient was a 35-year-old woman who
had SD since age 14 years that spread to the oromandibular
region starting at age 21. At examination we saw a patient
with segmental dystonia affecting the tongue and laryngeal
dystonia of the adductor subtype. No cervical dystonia or
writer’s cramp was present. She was treated with botulinum
toxin injections for SD, with good response lasting 3 months,
and trihexyphenidyl 8 mg a day, with moderate benefit for
involuntary tongue movements. Family history was negative
for dystonia. We encountered 4 additional sequence variants
in the 50 UTR and intronic regions of THAP1: c.-237_-
236GA>TT had a frequency of 4.5% in SD cases and 2.2%
in the control group (P ¼ .22); c.71þ9C>A was present in
0.5% of the control group but was not found in the patient
group; c.71þ126T>C (rs71521601) had a frequency of
5.5% in patients and 3.8% in controls (P ¼ .49); and
L E T T E R S : N E W O B S E R V A T I O N S
1 patient carried a new variant in intron 1, c.71þ18C>T,
not found in the control population. This variant was not
predicted to affect splicing. We did not find a significant dif-
109
ference in frequency of any of these variants; however, sam-
67%
ple size was small, making data pooling of homogeneous
patient groups warranted. These variants are candidates for
16%a future association studies.
16%a Xiao et al5 previously screened 460 American SD patients
18% and found 2 nonsynonymous genetic variants (0.43%) with
10% late-onset SD in nonfamilial cases.5 This low prevalence of
6% THAP1 genetic variation in SD dystonia patients is compa-
1%
rable with other focal and segmental dystonia groups.5–7 In
1%
contrast, THAP1 mutations are causal for up to 25% of
familial cases with generalized dystonia with prominent la-
ryngeal involvement.4
Most mutations causing early-onset DYT6 were found in
the DNA-binding THAP domain.7 In the 2 previously
described focal SD patients,5 mutations were in the coiled coil
domain of THAP1. In this domain, additional rare synony-
mous variants were found in a control subject and in 2 focal
cervical dystonia patients.7 These observations might indicate
a less pathogenic role of mutations affecting this region. The
Ser51Gly change identified here affects an amino acid highly
conserved from man to chicken (Homologene: 10005; http://
www.ncbi.nlm.nih.gov/homologene) in the THAP domain.
Our screening of Dutch SD patients attending the botuli-
num toxin treatment clinic confirms that mutations in the
DYT6 gene THAP1 are present but rare in focal and seg-
mental SD patients.
Justus L. Groen, MD,1,2 Eren Yildirim, MSs,1
Katja Ritz, MSc,2 Frank Baas, MD, PhD,1
Jacobus J. van Hilten, MD, PhD,3
Freerk W. van der Meulen, MD, PhD,4
Ton P. Langeveld, MD, PhD,5
and Marina A.J. Tijssen, MD, PhD1*
Departments of 1Neurology and 2Neurogenetics,
Academic Medical Center, University of
Amsterdam, Amsterdam, The Netherlands;
3
Department of Neurology, Leiden University
Medical Centre, Leiden, The Netherlands;
4
Department of Otorhinolaryngology—Head and
Neck Surgery, Academic Medical Center,
University of Amsterdam, Amsterdam,
The Netherlands; and
5
Department of Otorhinolaryngology—Head and
Neck Surgery, Leiden University Medical Center,
Leiden, The Netherlands
References
1. Butler AG, Duffey PO, Hawthorne MR, Barnes MP. An epide-
miologic survey of dystonia within the entire population of
northeast England over the past nine years. Adv Neurol 2004;
94:95–99.
2. Blitzer A. Spasmodic dysphonia and botulinum toxin: experience
from the largest treatment series. Eur J Neurol 2010;17(Suppl 1):
28–30.
3. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the
THAP1 gene are responsible for DYT6 primary torsion dystonia.
Nat Genet 2009;41:286–288.
Movement Disorders, Vol. 26, No. 10, 2011 1953
L E T T E R S : N E W O B S E R V A T I O N S
4. Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ,
Saunders-Pullman R. Mutations in THAP1 (DYT6) in early-onset
dystonia: a genetic screening study. Lancet Neurol 2009;8:
441–446.
5. Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence var-
iants in primary dystonia. Neurology 2010;74:229–238.
6. Djarmati A, Schneider SA, Lohmann K, et al. Mutations in
THAP1 (DYT6) and generalised dystonia with prominent spas-
modic dysphonia: a genetic screening study. Lancet Neurol 2009;8:
447–452.
7. Groen JL, Ritz K, Contarino MF, et al. DYT6 dystonia: Mutation
screening, phenotype, and response to deep brain stimulation. Mov
Disord 2010;25:2420–2427.
Successful Deep Brain Stimulation
in a Case of Posttraumatic Tremor
and Hemiparkinsonism
Holmes tremor is the most common clinical presentation
of posttraumatic tremor caused by a midbrain lesion. It is
defined as a slow-frequency (<4.5 Hz), irregular resting and
intention tremor with a variable onset of weeks to months af-
ter the initial insult.1 The co-occurrence of parkinsonian and
cerebellar features reflects the combined lesioning of nigrostri-
atal and cerebellothalamic pathways in this condition. Here,
we describe the clinical course of a patient with posttraumatic
tremor presenting as tremor-dominant hemiparkinsonism,
which resulted from an isolated lesion of the nigrostriatal
pathway several weeks after a single closed-head injury.
The 31-year-old man slipped in his bathroom and sus-
tained a severe head trauma with a left hemisphere subdural
hemorrhage requiring surgical evacuation. He recovered from
an incomplete palsy of the left third cranial nerve and a slight
left-sided hemiparesis without neurological sequelae. Approx-
imately 2 months later, he gradually developed a violent rest-
------------------------------------------------------------
Additional Supporting Information may be found in the online version of
this article.
Current address for Marcus O. Pinsker: Department of Functional and
Stereotactic Neurosurgery, University of Freiburg, Germany.
Current address for Jens Volkmann: Department of Neurology, Julius-
Maximilians-University, Würzburg, Germany.
*Correspondence to: Jens Volkmann, Department of Neurology,
Julius-Maximilians-University, Würzburg, Germany;
volkmann_j@klinik.uni-wuerzburg.de
Relevant conflicts of interest/financial disclosures: René Reese,
Daniela Falk, and Marcus O. Pinsker received speaking honoraria from
Medtronic. Georg Ebersbach received honoraria for presentations and
advisory board activities from Boehringer Ingelheim Pharma,
Cephalon, Desitin Pharma, GlaxoSmithKline, Valeant, Novartis, Orion,
and Schwarz Pharma (UCB). H. Maximilian Mehdorn received
speaking honoraria and consultant fees from Medtronic. Günther
Deuschl received grant support for conducting a multicenter study.
Jens Volkmann received honoraria for lectures, consulting fees, and
grant support from Medtronic Inc.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 29 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23686
1954 Movement Disorders, Vol. 26, No. 10, 2011
ing and action tremor and moderate akinetic-rigid symptoms
of the left hemibody. The tremor frequency of 5–6 Hz and
the lack of an intention tremor or other cerebellar symptoms
were not compatible with the diagnosis of Holmes tremor,
and despite the slightly irregular and atypical tremor presen-
tation (Video), a diagnosis of a secondary, tremor-dominant
hemiparkinsonism was made. Repeated, high-resolution MRI
did not reveal any structural abnormality at the level of the
midbrain, basal ganglia, or thalamus after the initial insult or
during the subsequent course. A FDG-PET of brain glucose
metabolism was normal. 123-I-FP-CIT SPECT, however,
demonstrated reduced dopamine transporter binding in the
right brain hemisphere (Fig. 1). Treatment attempts with car-
bamazepine, valproic acid, propranolol, bornaprine, and clo-
zapine failed. From a combined dopaminergic treatment with
L-dopa/benserazide (up to 900 mg daily) and cabergoline (3
mg daily), the patient had only transient benefit. He was con-
sidered for deep brain stimulation because the tremor did not
allow him to work as a stockman and impaired most of his
daily activities. In the presurgical assessment, the patient
scored 31 points on the UPDRS motor score (tremor sub-
score, 8) in the off state, which did not change after a chal-
lenge with 200 mg of levodopa/benserazide.
Although the ventrointermediate (VIM) thalamic nucleus
is considered the standard surgical target for posttraumatic
tremors,2 in this case we also planned for functional map-
ping of the subthalamic nucleus (STN) because of the iso-
lated Parkinsonian syndrome. Surgical implantation of deep
brain electrodes following our published procedure3,4 took
place on May 26, 2005, after the patient had given informed
consent to this individual therapeutic trial. Intraoperative
high-frequency stimulation of the dorsolateral STN as identi-
fied by microrecordings resulted in a marked reduction of
contralateral rigidity, bradykinesia, and rest tremor, whereas
kinetic tremor persisted. VIM stimulation reduced tremor
but did not alleviate bradykinesia and rigidity. Therefore, it
was decided to implant permanent electrodes (model 3389,
Medtronic Inc., Minneapolis, MN) into both targets, which
were subsequently connected to a single pulse generator
(Kinetra, Medtronic Inc., Minneapolis, MN).
Postoperatively, resting tremor as well as akinetic-rigid
symptoms showed an immediate response to monopolar
STN-HFS with low current amplitudes. Kinetic tremor was
absent for several weeks after surgery, probably because of a
microlesioning effect, but a gradual return, which could not
be treated by reprogramming of STN-HFS, necessitated addi-
tional monopolar stimulation of the VIM. The patient discon-
tinued all oral medication and experienced a stable treatment
response of combined neurostimulation for the subsequent 3
years without any adverse effects. Because of an infection of
the stimulation system, the patient had to be explanted 5
years after initial implantation. Parkinsonian symptoms rap-
idly worsened to the preoperative state. Six months later, the
stimulation system was reimplanted, and the patient achieved
the former symptom relief (STN: Cþ2 ;2.6 V;60 ls/130 Hz;
VIM: Cþ5 ;1.5 V;90 ls/130 Hz). Clinical evaluation 1 week
after second implantation resulted in the following UPDRS
scores: STNoff/VIMoff—motor score, 25 (tremor score, 8);
STNon/VIM off—motor score, 12 (tremor score, 3); STNon/
VIMon—motor score, 8 (tremor score, 0).

FIG. 1. 123-I-FP-CIT SPECT superimposed on patient’s preoperative
cranial MRI demonstrates the virtually complete cessation of striatal
dopamine transporter binding in the right brain hemisphere.
Our case demonstrates, that combined neurostimulation
of the VIM and STN can be successful in treating posttrau-
matic tremor and hemiparkinsonism, even in the long term.
VIM stimulation is a monosymptomatic treatment for
tremor, and STN stimulation may alleviate parkinsonian fea-
tures in this setting. This observation is consistent with a
previous case of a patient with Holmes tremor, in whom
VIM stimulation reduced intention tremor, but suppression
of resting tremor required additional STN-HFS.5 Our case,
however, is unique because of the lack of any macroscopic
brain lesion on MRI and the dopaminergic striatal denerva-
tion proven by SPECT, which most probably resulted from
an isolated axonal shearing trauma of the nigrostriatal path-
way. Zijlmans et al6 described a similar patient with a
tremor syndrome resulting from a complete striatal dopami-
nergic denervation after a traumatic substantia nigra hemor-
rhage. Interestingly, this patient had no akinetic-rigid
symptoms, probably because of the hemorrhagic lesion
extending into the STN, and the tremor responded well to a
subsequent thalamotomy.
Legends to the Video
Video Segment 1. STNoff/VIMoff—the patient presents
with a tremor-dominant left hemibody parkinsonian syn-
drome without any sign of cerebellar dysfunction 1 week af-
ter second implantation of the stimulation system.
Video Segment 2. STNon/VIMoff—bradykinesia and rigid-
ity are markedly reduced, but alternating movements are still
impaired by a kinetic tremor.
Video Segment 3. STNon/VIMon—additional VIM stimu-
lation virtually stops tremor and now allows the patient to
perform smooth alternating hand movements.
L E T T E R S : N E W O B S E R V A T I O N S
René Reese, MD,1 Jan Herzog, MD, PhD,1
Daniela Falk, MD,2 Ulf Lützen, MD,3
Marcus O. Pinsker, MD, PhD,2
H. Maximilian Mehdorn, MD, PhD,2
Georg Ebersbach, MD, PhD,4 Günther Deuschl, MD, PhD,1
and Jens Volkmann, MD, PhD1*
Departments of 1Neurology, 2Neurosurgery, and
3
Nuclear Medicine, Universitätsklinikum
Schleswig-Holstein, Kiel, Germany; and
4
Movement Disorders Clinic, Beelitz-Heilstaetten,
Germany
References
1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement
Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov
Disord 1998;13(Suppl 3):2–23.
2. Krauss JK, Jankovic J. Head injury and posttraumatic movement
disorders. Neurosurgery 2002;50:927–939.
3. Schrader B, Hamel W, Weinert D, Mehdorn HM. Documentation
of electrode localization. Mov Disord 2002;17(Suppl 3):
S167–S174.
4. Herzog J, Hamel W, Wenzelburger R, et al. Kinematic analysis of
thalamic versus subthalamic neurostimulation in postural and
intention tremor. Brain 2007;130:1608–1625.
5. Romanelli P, Bronte-Stewart H, Courtney T, Heit G. Possible
necessity for deep brain stimulation of both the ventralis interme-
dius and subthalamic nuclei to resolve Holmes tremor. Case report.
J Neurosurg 2003;99:566–571.
6. Zijlmans J, Booij J, Valk J, Lees A, Horstink M. Posttraumatic tremor
without parkinsonism in a patient with complete contralateral loss of
the nigrostriatal pathway. Mov Disord 2002;17:1086–1088.
Lack of Association of the UCHL-1
Gene with Parkinson’s Disease in a
Greek Cohort: A Haplotype-Tagging
Approach
Ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) is an
abundant neuron-specific deubiquitinating enzyme in the
human brain that is essential for the cellular clearance of
abnormal proteins.1
The amino acid substitution of serine to tyrosine (S18Y)
in the UCHL-1 gene has been found to modify enzymatic
activity and to be associated with neurodegenerative
------------------------------------------------------------
*Correspondence to: Georgios M. Hadjigeorgiou, gmhadji@med.uth.gr
Relevant conflicts of interest/financial disclosures: Nothing to report.
This work was supported in part through the Research Committee of
the University of Thessaly (Code: 2845), Institute of Biomedical
Research & Technology, CERETETH (Code: 01-04-207), and PENED
03 grant 650, ‘‘Genetic Variations of PD Associated Genes in the
Greek Population and their Functional Analysis,’’ from the Hellenic
Secretariat of Research and Technology (to D.V. and L.S.). Novartis
Hellas was a cosponsor of this grant.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 28 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23694
Movement Disorders, Vol. 26, No. 10, 2011 1955
L E T T E R S : N E W O B S E R V A T I O N S

Table 1. Chi-square and P values for allele, genotype, and haplotype frequencies (odds ratios and
their 95% confidence intervals are presented for the minor allele versus the major allele for all SNPs and for
haplotypes analyses)
Polymorphism Controls (%) Cases (%) v2 P value Odds ratio (95% CI)

rs5030732 (S18Y)
Genotype C/C 237 (57.4%) 233 (59.9%)
C/A 155 (37.5%) 135 (34.7%)
A/A 21 (5.1%) 21 (5.4%) 0.64 0.72
Allele C 629 (76.2%) 601 (77.2%)
A 197 (23.8%) 177 (22.8%) 0.11 0.73 0.95 (0.73–1.18)
rs3822050
Genotype A/A 355 (85.3%) 326 (82.7%)
A/G 57 (13.7%) 64 (16.3%)
G/G 4 (1%) 4 (1%) 1.04 0.63
Allele A 716 (90.9%) 767 (92.2%)
G 72 (9.1%) 65 (7.8%) 0.91 0.33 0.89 (0.61–1.30)
rs2060915
Genotype T/T 263 (64.6%) 254 (65.8%)
T/C 84 (20.6%) 77 (20%)
C/C 60 (14.8%) 55 (14.2%) 0.17 0.91
Allele T 610 (74.9%) 585 (75.8%)
C 204 (25.1%) 187 (24.2%) 0.15 0.69 0.95 (0.73–1.22)
rs10517002
Genotype A/A 154 (37.8%) 148 (39%)
A/C 187 (46%) 178 (46.8%)
C/C 66 (16.2%) 54 (14.2%) 0.69 0.7
Allele A 495 (60.8%) 474 (59.8%)
C 319 (39.2%) 319 (40.2%) 0.69 0.4 1.1 (0.87–1.37)
rs17528160
Genotype A/A 276 (66.8%) 271 (69%)
A/G 124 (30%) 108 (27.5%)
G/G 13 (3.2%) 14 (3.5%) 0.89 0.63
Allele A 676 (81.8%) 650 (82.7%)
G 150 (18.2%) 136 (17.3%) 0.16 0.68 1.05 (0.79–1.4)

Haplotype analysis

Haplotype ID rs5030732 rs3822050 rs2060915 rs10517002 rs17528160 Cases (%) Control (%) Chi-square P value Odds ratio (95% CI)

A C A T C A 37.2 39.8 0.86 0.35 0.89 (0.71–1.13)

B C A C A G 17.7 18.8 0.22 0.63 0.93 (0.69–1.24)
C A A T A A 17.7 17.5 0.007 0.93 1.01 (0.75–1.36)
D C A T A A 11 8.4 2.38 0.12 1.35 (0.92–1.99)
E C G T A A 9.9 8.8 0.39 0.53 1.13 (0.76–1.67)
F C A C C A 1.3 1.1
G A A C A G 0 0.2
H C A C C G 0.1 0
Global v2 (df ¼ 4) ¼ 6.12 Fisher’s P value ¼ 0.29

disorders.2 The possible protective effect of this polymor-
phism on Parkinson’s disease (PD) has been investigated in
several genetic association studies with contradictory results
(for a complete review, see http://www.pdgene.org)
We investigated the association of UCHL-1 gene tagging
single-nucleotide polymorphisms (tSNPs)/haplotypes with PD
in Greek patients and controls.
Three hundred and ninety-nine sporadic PD patients (169
women, 230 men; mean age at onset, 65 6 9.6 years; age at ex-
amination, 69.4 6 8.7 years) and 420 healthy controls (191
women, 229 men; mean age at examination, 69 6 12.8 years)
matched for age, sex, and ethnic origin were studied. All subjects
were residents of Thessaly and Athens. After approval from the
institutional review board and collection of informed consent
from patients and controls, genomic DNA was extracted from
peripheral blood leukocytes. A total of four intronic tSNPs
(rs3822050, rs2060915, rs10517002, rs17528160) were
selected (http://www.hapmap.org). tSNPs capture 90% of the
genetic variation across the UCHL-1 locus in whites. We also
studied the common S18Y variant (rs5030732).
Taqman Assays-by-Design SM SNP Genotyping (Applied
Biosystems, Foster City, CA)–based assays were employed
for allelic discrimination of all 5 SNPs. Pair-wise D0 , r2,
and Hardy–Weinberg equilibrium measurements were made
using the program JLIN (http://www.genepi.com.au/projects/
jlin). Four patients and 4 controls were excluded from

1956 Movement Disorders, Vol. 26, No. 10, 2011


analysis because their DNA did not work for all SNPs. For
every SNP that we studied, there is a different rate for geno-
type failures, but this still remains very low, <3%. The dis-
tribution of genotype frequencies for all 5 SNPs investigated
was consistent with Hardy–Weinberg expectations in both
the control and the patient groups (P > .05). A single block
of LD was identified in UCHL-1 encompassing 5 kb.
Genotype-specific odds ratios, 95% confidence intervals,
and P values were computed by unconditional logistic regres-
sion. The distribution of the allele and genotype frequencies of
the studied SNPs did not differ significantly between PD
patients and controls (Table 1). Prospective power calculations
made by the genetic power calculator program CaTS (http://
www.sph.umich.edu/csg/abecasis/cats) indicated 90% power to
detect an odds ratio of 1.65 (heterozygous) and 2.85 (homozy-
gous). Multilocus analysis (http://analysis.bio-x.cn) showed the
presence of 5 haplotypes (with frequency above 5%). The hap-
lotype distribution did not differ significantly between PD
cases and controls (Table 1).
Using linear models, we found no associations between
individual SNPs or haplotypes and age at onset. Stratifica-
tion for PD onset also revealed no association between the
SNPs and the risk for PD. Particularly for the polymorphism
S18Y that previous studies revealed an association between
the Y allele and a decreased risk for PD with earlier onset,
we found no association (OR, 0.67; 95% CI, 0.53–1.21).
The main conclusion of our study is that common genetic var-
iants in the UCHL-1 gene do not influence PD risk in our popu-
lation, albeit rare SNPs in the UCHL-1 gene may also influence
PD susceptibility. So far, only 2 studies have used the haplotype-
tagging approach that was employed in the current study.3,4
Twelve genetic association studies of the S18Y variant
have been performed (for a review, see http://www.pdge-
ne.org). Two meta-analyses and 1 pooled analysis have also
been performed to summarize the association between the
S18Y variant and Parkinson’s disease across studies.3,5,6 Our
results are in accordance with 2 large genetic association
studies.3,7 Healy et al3 used the tagging approach, similar to
our own study. Sutherland et al4 also used a haplotype-
tagging approach as well as examining multiple candidate
genes, and the UCHL-1 gene was amongst them. Two tag-
ging SNPs that were examined in that study are included in
our study as well, and an association between rs10517002
and PD was observed. Our findings do not support this asso-
ciation; however, the results concerning S18Y and
rs2060915 are consistent with our data.
To date, several independent and combined genome-wide
association studies (GWAS) have investigated the genetic
susceptibility to Parkinson’s disease (for details, see http://
www.pdgene.org). These studies implicated several genes as
PD risk loci such as SNCA, MAPT,8 and more recently a
new association with the HLA region.9 The UCHL-1 gene
was not found to be associated with PD in these studies.
The analysis of GWAS data available through dbGAP sup-
ports our negative findings (data available on request).
Georgia Xiromerisiou, MD,1,2 Elli Kyratzi, MSc,3
Efthimios Dardiotis, MD,1,2 Maria Bozi, MD,4,5
Vana Tsimourtou, MD,1 Eleftherios Stamboulis, MD,5
Styliani Ralli, MD,1 Demetrios Vassilatis, PhD,3
Vanessa Gourbali, MD,1 Persa-Maria Kountra, MD,1
Kostas Fountas, MD,2 Alexandros Papadimitriou, MD,1
L E T T E R S : N E W O B S E R V A T I O N S
Leonidas Stefanis, MD,3,5 and
Georgios M. Hadjigeorgiou, MD1,2*
1
Department of Neurology, University Hospital of
Larissa, Faculty of Medicine, University of
Thessaly, Larissa, Greece; 2Institute of Biomedical
Research & Technology, CERETETH, Larissa,
Greece; 3Biomedical Research Foundation of the
Academy of Athens, Athens, Greece; 4General
Hospital of Syros, Syros, Greece; 5Department of
Neurology, University of Athens Medical School,
Athens, Greece
References
1. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT, Jr., The UCH-
L1 gene encodes two opposing enzymatic activities that affect
alpha-synuclein degradation and Parkinson’s disease susceptibility.
Cell. 2002;111:209–218.
2. Kyratzi E, Pavlaki M, Stefanis L. The S18Y polymorphic variant of
UCH-L1 confers an antioxidant function to neuronal cells. Hum
Mol Genet. 2008;17:2160–2171.
3. Healy DG, Abou-Sleiman PM, Casas JP, et al. UCHL-1 is not a Par-
kinson’s disease susceptibility gene. Ann Neurol. 2006;59:627–633.
4. Sutherland GT, Halliday GM, Silburn PA, et al. Do polymor-
phisms in the familial Parkinsonism genes contribute to risk for
sporadic Parkinson’s disease? Mov Disord. 2009;24:833–838.
5. Maraganore DM, Lesnick TG, Elbaz A, et al. UCHL1 is a Parkin-
son’s disease susceptibility gene. Ann Neurol. 2004;55:512–521.
6. Ragland M, Hutter C, Zabetian C, Edwards K. Association
between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1)
S18Y variant and Parkinson’s disease: a HuGE review and meta-
analysis. Am J Epidemiol. 2009;170:1344–1357.
7. Hutter CM, Samii A, Factor SA, et al. Lack of evidence for an
association between UCHL1 S18Y and Parkinson’s disease. Eur J
Neurol. 2008;15:134–139.
8. Simon-Sanchez J, Schulte C, Bras JM, et al. (2009)Genome-wide
association study reveals genetic risk underlying Parkinson’s disea-
se.Nat Genet. 41:1308–1312.
9. Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic varia-
tion in the HLA region is associated with late-onset sporadic Par-
kinson’s disease. Nat Genet. 42:781–785.
Development of Holmes’ tremor
following hemi-cerebellar infarction
We report the case of a 36-year-old patient who devel-
oped unilateral Holmes’ tremor following hemicerebellar
------------------------------------------------------------
Additional Supporting Information may be found in the online version of
this article.
*Correspondence to: John-Stuart Brittain, Department of Physiology,
Anatomy & Genetics University of Oxford, Oxford, United Kingdom;
john-stuart.brittain@eng.ox.ac.uk
Funding agencies: This work received suppport from the UK Medical
Research Council, the Norman Collisson Foundation, Charles Wolfson
Charitable Trust, and the Oxford Biomedical Research Centre.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 3 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23704
Movement Disorders, Vol. 26, No. 10, 2011 1957
L E T T E R S : N E W O B S E R V A T I O N S

FIG. 1. A: Electromyographic traces and spectral analysis from extensor digitorum communis (EDC) muscles during rest and postural conditions. B:
Preoperative coronal T2-MR highlighting a hyperintense region about the left ventrolateral thalamus. C: Preoperative axial T2-MR overlaid with post-
operative CT, coregistered using Radionics ImageFusion. Arrow indicates location of the deep brain stimulation electrode. D: Preoperative axial MR
images of patient taken at 6-mm slices traversing the cerebellar hemispheres.

infarction. The patient proved unresponsive to levodopa
therapy and was subsequently referred for deep brain stimu-
lation (DBS) targeting the ventro-oralis posterior (Vop) nu-
cleus and zona incerta (ZI). The procedure proved successful
in abolishing rest and postural tremors, with partial suppres-
sion of intention tremor (though not ataxia). The history of
this patient’s remarkable hemicerebellar lesion and subse-
quent surgical response is summarized below with discussion
on the implications for tremor pathophysiology.
The patient was originally admitted after suffering a right
vertebral artery occlusion, leading to infarction of the ipsilat-
eral cerebellum extending toward the midbrain (Fig. 1D). The
patient remained in a coma for 4 days and subsequently made
a good recovery under rehabilitation, emerging with some
right-sided hemiparesis and dysarthria. Four months after the
stroke, the patient developed right-sided ataxia with concur-
rent intention tremor, progressing quickly to include rest and
postural tremors. Following stabilization of symptoms, a di-
agnosis of Holmes’ tremor was made. Subsequent MR imag-
ing revealed an additional mixed low/iso-intense region on T1
(hyperintense on T2) about the left ventrolateral thalamus
(Fig. 1B) extending into the posterior limb of the cerebellar
peduncle. The patient was unresponsive to levodopa (Sine-
met) and was subsequently referred for DBS in an attempt to
manage the tremor component. At the time of referral, medi-
cation constituted aspirin (75 mg), clopidogrel (75 mg), biso-
prolol (75 mg), perindopril (8 mg), escitalopram (15 mg),
pravastatin (20 mg) and Baclofen (30 mg).
The trajectory chosen for DBS electrode implantation trav-
ersed the left Vop and ZI (Fig. 1C), 2 structures that have pro-
ven efficacious for complex tremor suppression.1
Electromyography (EMG) of the wrist extensors demonstrated
a 3- to 4-Hz tremor (Fig. 1A), typical of Holmes’ tremor.2
Titrated high-frequency stimulation (HFS) using a Medtronic
3387 electrode (4.1 V, 120 ls, 100 Hz, contacts 0–3þ) proved
successful in suppressing resting and postural tremors, with
intention tremor suppressed to a lesser extent. Mean tremor
scores (double-blind assessment ON versus OFF stimulation)
were reduced by 89% at rest (4.5 to 0.5, Bain rating scale3),
90% for postural (4.8 to 0.5), and 32% for intention (7.7 to 5).
Holmes’ tremor provides a fascinating manifestation of
tremor phenotypes we would normally consider distinct enti-
ties. Taken in isolation, this report suggests that the separate
components of Holmes’ tremor cannot be generated from sin-
gle or multiple oscillators in the ipsilateral cerebellum. In this
case of hemicerebellar infarction (and indeed that of hemicere-
bellectomy4), we observed that the central nervous system of
the human is capable of producing resting, postural, and
intention tremors in the absence of unilateral cerebellar input.
Indeed, it is highly probable that it is the imbalance in baso/
cerebellocortical networks that permit the escalation of an
aberrant tremor rhythm.5 Moreover, despite proving effica-
cious in the treatment of multiple sclerosis tremors,1 stimula-
tion of Vop/ZI appears less effective at suppressing intention
tremor in the extreme case of severe hemicerebellar infarction.
The reported case of Holmes’ tremor following hemicerebel-
lectomy4 portrayed a patient who subsequently developed a
classic Parkinsonian rest tremor contralateral to cerebellar abla-
tion, with a complex mix of resting, postural, and intention
tremors on the ipsilateral side. The difference in frequency of
the resting component led the authors to conclude that the cere-
bellum could not be the originator of the parkinsonian resting
tremor rhythm. This seminal case drew important conclusions
about the origins of the classic parkinsonian tremor and

1958 Movement Disorders, Vol. 26, No. 10, 2011


supports the observation that the distinct components of
Holmes’ tremor can manifest in the complete absence of cerebel-
lar input.
DBS has previously been investigated in the treatment of
Holmes’ tremor where, notably, Romanelli et al6 reported the
case of a levodopa unresponsive patient who achieved complete
suppression of intention tremor and partial suppression of pos-
tural tremor following DBS of the ventralis intermedius nucleus.
Subsequent implantation of an additional STN electrode is
reported to have resolved the residual resting and postural trem-
ors. Unlike our case, however, the patient was reported to have
shown no obvious signs of discrete brain injury.
Taken together, these reports support the notion that (1) the
human central nervous system is capable of producing resting,
postural, and intention tremor rhythms in the complete ab-
sence of unilateral cerebellar input, (2) disruption to the cere-
bellothalamic pathway appears necessary for the manifestation
of Holmes’ tremor, and (3) localized neural intervention ameli-
orates differential aspects of Holmes’ tremor, suggesting that
disruption to the nigrostriatal and cerebellothalamic pathways
produces selective alteration in tremor manifestation.
John-Stuart Brittain, PhD,1* Ned Jenkinson, PhD,2
Peter Holland, BA,2 Raed A. Joundi, BSc,1
Alex L. Green, MD,1,2 and Tipu Z. Aziz, DMedSci2
1
Department of Physiology, Anatomy & Genetics,
University of Oxford, Oxford, United Kingdom;
2
Functional Neurosurgery and Experimental
Neurology, Nuffield Department of Surgical Sciences,
University of Oxford, Oxford, United Kingdom
References
1. Bittar RG, Hyam J, Nandi D, et al. Thalamotomy versus thalamic
stimulation for multiple sclerosis tremor. J Clin Neurosci 2005;12:
638–642.
2. Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee.Consen-
sus statement of the Movement Disorders Society on tremor. Mov
Disord 1998;13:2–23.
3. Bain PG, Findley LJ, Atchison P, et al. Assessing tremor severity.
J Neurol Neurosurg Psychiatry 1993;56:868–873.
4. Deuschl G, Wilms H, Krack P, Wurker M, Heiss W-D.Function of
the cerebellum in parkinsonian rest tremor and Holmes’ tremor.
Ann Neurol 1999;46:126–128.
5. Raethjen J, Deuschl G. Tremor. Curr Opin Neurol 2009;22:
400–405.
6. Romanelli P, Bronte-Stewart H, Courtney T, Heit G.Possible neces-
sity for deep brain stimulation of both the ventralis intermedius
and subthalamic nuclei to resolve Holmes’ tremor. J Neurosurg
2003;99:566–571.
L E T T E R S : N E W O B S E R V A T I O N S
Palatal Tremor Visualized by
Cine MRI
Palatal tremor is a rhythmic involuntary movement of the
soft palate caused by lesions within the Guillain-Mollaret tri-
angle, which comprises the red nucleus, inferior olive, and
dentate nucleus.1 Symptomatic forms of palatal tremor can
result from cerebrovascular disease, trauma, neuroinflamma-
tion, malignoma, or neurodegeneration including progressive
ataxia and palatal tremor syndrome and may also be associ-
ated with GFAP gene mutations causing Alexander’s dis-
ease.2 In contrast to essential forms of palatal tremor, in
secondary forms, ear clicks may be absent, and adjacent
muscles can also be affected, causing combinations of oculo-
pharyngeal-laryngeal-palatal tremor. ENT assessment may
be helpful to evaluate the range of movements.3
MRI often reveals hypertrophy of the inferior olive, which
is thought to be the origin of the 0.5- to 3-Hz rhythmic dis-
charges. Recent developments in morphological neuroimaging
techniques enable more accurate demonstration of the under-
lying structural alterations of brain parenchymal lesions. Fur-
thermore, very fast MRI sequences, for example, 2D FLASH
(Fast Low Angle SHot), offer the capability of exceeding
purely morphological imaging, also depicting dynamic struc-
tural displacements such as tissue movement. Originally, this
novel technique was developed for cardiac imaging and has
been successfully applied to depict myocardial infarcts and
cardiac wall motion abnormalities.4–6
In this study, we used for the first time cerebral cine MRI in
order to capture the movements in a case of complicated pala-
tal tremor. Our patient, a 72-year old man with a medical his-
tory of hypertension, hyperlipoproteinemia, and nicotine
abuse, presented with sudden onset of dysarthria, dysphagia,
and gait difficulties. After a few days, he also developed invol-
untary rhythmic movements of the soft palate. Ear clicks were
absent. There was, however, synchronous involvement of ad-
jacent pharyngeal, laryngeal, and facial muscles and extraocu-
lar muscles (see Video 1). Applying a balanced turbo field
echo (BTFE) cine MRI sequence (slice thickness, 9 mm; TR,
2.1 ms; TE, 1.0 ms; flip angle, 40 ; FOV, 320  384; in-plane
resolution, 1.2  1.2 mm2), we could demonstrate the dynam-
ics of these complex movements (see Video 2). A routine MRI
workup revealed ischemic lesions affecting the Guillain-Mol-
laret triangle, presenting as signal hyperintensity on T2-
weighted as well as fluid attenuated inversion recovery MRI.
We wish to present recent developments and highlight the
potential of fast cine MRI in combination with iterative image
------------------------------------------------------------
*Correspondence to: Susanne A. Schneider, Department of
Neurology, University Luebeck, Luebeck, Germany;
susanne.schneider@neuro.uni-luebeck.de
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 11 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23717
Movement Disorders, Vol. 26, No. 10, 2011 1959
L E T T E R S : N E W O B S E R V A T I O N S
reconstruction, permitting the acquisition of real-time MRI at a
temporal resolution of 20–30 ms at very high spatial resolution
(up to 1.5–2.0 mm).7 Not only is this technique revolutionizing
cardiovascular in vivo diagnostics and reveals insights into flow
dynamics of CSF,7–9 but it may well prove to be a useful tool in
adding to the understanding of complicated movement disor-
ders in the future. Cine MRI may help in the study of move-
ment disorders such as laryngeal and pharyngeal movement
disorders or disorders of pelvic floor motion and in a variety of
situations in which other means of investigation including clini-
cal observation, video recordings, or electrophysiological stud-
ies are impractical, invasive, or technically challenging. We
encourage our colleagues to apply novel cine MRI techniques
in patients with complex movements.
Legends to the Video
Video 1. On clinical examination, full view shows rhyth-
mic movements of the larynx and ocular movements with
nystagmus to the right, affecting both eyes. On intraoral
assessment, there is palatal tremor. Video endoscopy shows
laryngeal involvement.
Video 2. Balanced turbo field echo (BTFE) cine MRI (40-sec-
ond cycle; 1.3 Hz/slice) demonstrates the dynamics of rhythmic
pharyngeal and laryngeal contractions because of the pharyn-
geal-laryngeal-palatal tremor. Inferior olive hypertrophy, often
associated with palatal tremor, was not evident in this case. A
time stamp conveys the time scale of the movements.
Jens T. Wuerfel, MD,1 Guenter Seidel, MD,2
Uwe Melchert, PhD,1 Andreas Sprenger, PhD,2
Cathrin Hansmann, MD,2 Peter Trillenberg, MD,2
Dirk Petersen, MD,1 Rainer Schoenweiler, MD,3 and
Susanne A. Schneider, MD, PhD2*
1
Institute of Neuroradiology and 2Department of
Neurology, University Luebeck, Luebeck,
Germany; and 3Department of Phoniatrics and
Pediatric Audiology (Speech, Language, Voice,
Swallowing, and Hearing Disorders),
University Clinic of Schleswig-Holstein,
Campus Luebeck, Germany
References
1. Deuschl G, Toro C, Valls-Sole J, et al. Symptomatic and essential
palatal tremor. 1. Clinical, physiological and MRI analysis. Brain
1994;117:775–788.
2. Samuel M, Torun N, Tuite PJ, et al. Progressive ataxia and palatal
tremor (PAPT): clinical and MRI assessment with review of palatal
tremors. Brain 2004;127:1252–1268.
3. Finke C, Jumah MDJT, Ploner CJ. An endoscopic view of sympto-
matic palatal tremor. Neurology 2010;74:e16.
4. Zhang S, Block KT, Frahm J. Magnetic resonance imaging in real
time: Advances using radial FLASH. J Magn Reson Imaging 2010;
31:101–109.
5. Frahm J, Haase D, Matthaei D. Rapid three-dimensional MR imaging
using the FLASH technique. J Comput Assist Tomogr 1986;10:363–368.
6. Miller S, Huppert PE, Naegele T, et al. MR tomography studies of
myocardial function and perfusion after myocardial infarct. Rofo
1997;167:399–405.
7. Penn RD, Linninger A. The physics of hydrocephalus. Pediatr Neu-
rosurg 2009;45:161–174.
8. Sweetman B, Xenos M, Zitella L, et al. Three-dimensional compu-
tational prediction of cerebrospinal fluid flow in the human brain.
Comput Biol Med 2011;41:67–75.
1960 Movement Disorders, Vol. 26, No. 10, 2011
9. Algin O, Hakyemez B, Parlak M. The efficiency of PC-MRI in di-
agnosis of normal pressure hydrocephalus and prediction of shunt
response. Acad Radiol 2010;17:181–187.
Fragile X–Associated Tremor
Ataxia Syndrome sine Tremor
Fragile X syndrome is caused by a trinucleotide repeat
expansion of greater than 200 CGG repeats in the 50 end of
the familial mental retardation 1 gene (FMR1). Expansion of
50–200 CGG repeats is associated with fragile X tremor-
ataxia syndrome (FXTAS), characterized by cerebellar ataxia
and tremor, with parkinsonism and cognitive deficits. The
condition, however, is rare on FMR1 screening of cohorts of
idiopathic ataxia, tremor, or parkinsonism.1,2 FXTAS is
more common in males, whereas female premutation carriers
more commonly manifest with premature menopause and
ovarian failure, occurring in 16%.3,4
The MRI finding of increased T2 signal change in the
middle cerebellar peduncles (MCPs) can be found in 82%
of FXTAS. These MRI findings, although useful in the di-
agnosis of the tremulous FXTAS patient, are less discrimi-
natory in predominately ataxic individuals, with MCP change
reported in multiple system atrophy, spinocerebellar ataxia
(SCA), and dentatorubro-pallidoluysian atrophy.5 Tremor,
although a major clinical feature of FXTAS, can be absent in
20%.6 The absence in an individual FXTAS subject to both
tremor and typical signal change in the MCP is uncommon
and presents a considerable challenge.
Here we present 2 cases of FXTAS sine tremor—1 case
had typical MCP signal change, the other lacked this diag-
nostic radiological feature. Both cases were confirmed FMR1
premutation carriers on subsequent genetic testing. There
was no family history of fragile X syndrome in either case.
Case 1 was a 57-year-old man with 4 years of progres-
sive incoordination, dysarthria, falls, and recent memory
decline.
Examination revealed upper limb dysdiadochokinesia
and dysmetria. There was no rest, postural, or kinetic
tremor. Eye movements showed hypometric saccades with
gaze-evoked horizontal nystagmus. There was impaired
verbal memory and working memory, but normal executive
function, visual memory, and visuospatial performance. The
patient was examined over a 2-year period, and there was
never any indication of tremor (see video clip 1).
The patient’s brother, of a similar age, had also experi-
enced balance difficulty. On direct questioning, there was
------------------------------------------------------------
*Correspondence to: Nin Bajaj, Department of Neurology, Queens
Medical Centre, Nottingham, United Kingdom; nin.bajaj@nuh.nhs.uk
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 31 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23718

FIG. 1. Normal FP-CIT in case 1 (A) and case 2 (B). C: MRI of brain (FLAIR sequence) showing cerebellar atrophy with increased signal in the MCP
in case 1 (arrowhead). D: No MCP signal increase in case 2.
also a high incidence of premature ovarian insufficiency
among the patient’s female relatives, leading to menopause
in the third or fourth decade of life. This, together with the
MCP sign on MRI, prompted testing for FXTAS.
Case 2 was a 67-year-old man who gave a history of 2
years of leg fatigue on walking, progressive unsteadiness,
and 1 year of memory decline.
Eye movements were normal. There was no rest, postural,
or kinetic tremor. There was mild bradykinesia of alternat-
ing movements of the left hand, dysdiadochokinesia of the
left hand more than the right, and unsteadiness on heel–toe
walking. Gait was broad-based, and pull test showed abnor-
mal postural reflexes (video clip 2).
Cognitive testing showed moderate reduction in verbal
memory and working memory, mild reduction in visual
memory, mild visuospatial abnormality, and normal execu-
tive function.
Thyroid function, full blood count, autoimmune screen,
paraneoplastic screen, and celiac serology were negative or
normal. Genetic testing for SCA-1, -2, -3, -6, -7, -12, and -
17 and Friedreich’s ataxia was negative. CSF examination
and nerve conduction/electromyography in case 1 were
normal.
A 123I-/V-cu-fluoro-propyl-2b-carbomethoxy-3b-(4-iodo-
phenyl) nortropane ([123I] FP-CIT) SPECT of the brain was
normal in both patients (Fig. 1A,B). MRI in case 1 revealed
T2-weighted signal change in the middle cerebellar peduncles
and a mild degree of cerebellar atrophy (Fig. 1C). MRI
imaging in case 2 showed marked cortical and midbrain at-
rophy. No MCP high signal was seen (Fig. 1D).
Southern analysis of the FMR1 gene revealed an unmethy-
lated CGG expansion of 100 repeats in case 1 and 87 unme-
thylated CGG repeats in case 2, confirming FXTAS (normal,
<50 repeats; intermediate, 50–58 repeats; premutation, 59–
200 [unmethylated] repeats; full mutation, >200 methylated
repeats).
One of these patients, case 1, had definite FXTAS accord-
ing to the current diagnostic criteria (1 major clinical crite-
rion of gait ataxia and 1 major radiological criterion of
MCP signal change). Case 2 would have only been possible
FXTAS according to current clinical criteria, with 1 major
clinical criterion of cerebellar gait ataxia and 1 minor radio-
L E T T E R S : N E W O B S E R V A T I O N S
logical criterion of minor MRI lesions involving cerebral
white matter with moderate to severe generalized brain atro-
phy. Both cases lacked the major clinical criterion of tremor,
and this led to the diagnosis of FXTAS being overlooked
initially.
These cases highlight several important lessons. First, cases
of FXTAS can be mimics of idiopathic late-onset cerebellar
ataxia with absence of tremor. Second, the MRI scan may not
be helpful. Third, a positive history of premature ovarian fail-
ure in female relatives should be sought and genetic testing of
at risk individuals offered with appropriate counseling about
fertility and the future risk of having children with fragile X
syndrome. Thus, unless the diagnosis of FXTAS is actively con-
sidered and tested for genetically, it might be missed.
Legends to the Video
Video—Case 1. Fatiguable decrement of repetitive finger
taps left hand. Dysmetria and dysdiachokinesia bilaterally.
Broad-based gait and heel–toe ataxia.
Video—Case 2. Hyperpronation of outstretched hand.
Irregularity of repetitive movements left arm. Left-sided dys-
diadochokinesia. Broad-based ataxic gait.
Nin Bajaj, PhD,1* Derek Soon, MRCP,1 and
Niall Quinn, MD2
1
Department of Neurology, Queens Medical
Centre, Nottingham, United Kingdom; and 2Sobell
Department of Motor Neuroscience and
Movement Disorders, Institute of Neurology,
London, United Kingdom
References
1. Reis AH, Ferreira AC, Gomes KB, et al. Frequency of FMR1 pre-
mutation in individuals with ataxia and/or tremor and/or parkin-
sonism. Genet Mol Res 2008;7:74–84.
Movement Disorders, Vol. 26, No. 10, 2011 1961
L E T T E R S : N E W O B S E R V A T I O N S
2. Kamm C, Healy DG, Quinn NP, et al. European Multiple System
Atrophy Study Group. The fragile X tremor ataxia syndrome in
the differential diagnosis of multiple system atrophy: data from the
EMSA Study Group. Brain 2005;128:1855–1860.
3. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor,
parkinsonism, and generalized brain atrophy in male carriers of
fragile X. Neurology 2001;57:127–130.
4. Berry-Kravis E, Abrams L, Coffey SM, et al. Fragile X-associated
tremor/ataxia syndrome: clinical features, genetics, and testing
guidelines. Mov Disord 2007;22:2018–2030.
5. Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X premu-
tation carriers: characteristic MR imaging findings of adult male
patients with progressive cerebellar and cognitive dysfunction.
AJNR Am J Neuroradiol 2002;23:1757–1766.
6. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premuta-
tion tremor/ataxia syndrome:molecular, clinical, and neuroimaging
correlates. Am J Hum Genet 2003;72:869–878.
Severe Intracranial Bleeding Related
to Vitamin K Antagonist-Ropinirole
Interaction
Bleeding is an adverse effect of vitamin K antagonists. The
risk of bleeding is increased if vitamin K antagonists is asso-
ciated with drugs that could increase the chances of hemor-
rhagic events such as aspirin, nonsteroidal anti-inflammatory
drugs, or heparin. Dopamine agonists are not reported to
increase the risk of bleeding related to vitamin K antago-
nists. Here we describe a case of severe intracranial hemor-
rhage related to an interaction between fluindione and
ropinirole, a dopamine agonist used in the treatment of
Parkinson’s disease.
A 64-year-old woman was admitted to our neurointensive
care unit for intracranial hemorrhage in the right cerebellar
hemisphere. Her previous medical history included recently
diagnosed Parkinson’s disease and multiple thrombophlebitis
with no known etiology. The patient had been prescribed an
oral anticoagulant (fluindione) for 10 years, since a second
episode of thrombophlebitis. The international normalized ra-
tio (INR) was checked twice a year over the 10-year period.
The INR values were very stable within the therapeutic range
(between 2 and 3). She never consulted for hemorrhage.
Two months before admission to the intensive care unit,
the patient was prescribed ropinirole in progressively
increasing doses (6 mg per day during the first month and 8
mg per day thereafter), in order to treat parkinsonism with
important tremor. One month after the introduction of the
ropinirole, the INR was 3.2, and as a consequence, the dos-
age of fluindione was halved (Fig. 1). One month later, the
patient suddenly presented the following symptoms: vomit-
ing, headache, and a progressively decreasing level of con-
sciousness. When the patient was admitted to the emergency
------------------------------------------------------------
*Correspondence to: Thomas Geeraerts, Coordination d’Anesthésie,
Hôpital Purpan, Toulouse, France; geeraerts.t@chu-toulouse.fr
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 25 April 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23733
1962 Movement Disorders, Vol. 26, No. 10, 2011
department, the Glasgow coma score was 3. Cerebral CT
scan showed an important hematoma in the right cerebellar
hemisphere with intraventricular hemorrhage. The INR was
4, the platelet count 178 G/L, and the partial prothrombin
time 31/31 seconds. An emergency reversal of vitamin K
antagonists was performed with intravenous prothrombin
complex concentrates (20 IU/kg) and vitamin K (10 mg).
The INR decreased to 1.1. Ventricular drainage was then
rapidly performed. After speaking to the patient’s family, no
recent changes in diet or habits were identified.
Afterward, parkinsonism was still observed. Use of ropi-
nirole was definitively stopped, and neurologist consultants
replaced it with L-dopa. Fluindione was also stopped, and
only prophylactic anticoagulant (enoxaparin, 40 mg per day)
was administered after verifying the absence of phlebitis.
The patients left the hospital for rehabilitation 2 months af-
ter her admission. Magnetic resonance imaging angiography
performed 4 months after intracranial bleeding found no evi-
dence of vascular abnormality.
Discussion
Intracranial hemorrhage is a life-threatening adverse reac-
tion of vitamin K antagonist use and is associated with a
high mortality rate. Anticoagulant drugs increase the risk of
intracranial hemorrhage by 7, with a direct relationship with
the INR level.1
INR is known to be very labile with diet modification,
and vitamin K antagonists are known to have several inter-
actions with other drugs. Our patient did not have any
recent diet modification and was only exposed to fluindione
and ropinirole. A case of INR increase without bleeding
complications after the administration of ropinirole in a
patient receiving warfarin has been reported.2 To our knowl-
edge, our case is the first to describe a major adverse drug
reaction (intracranial bleeding) due to overdose of vitamin K
antagonists related to ropinirole interaction. Vitamin K
antagonists are hydroxylated and reduced by cytochrome
P450.3 The R-enantiomer is metabolized by cytochrome
CYP1A2. Ropinirole is also metabolised by CYP1A2.4 Thus,
ropinirole–fluindione competition can occur, with the accu-
mulation of R-enantiomers of vitamin K antagonists. In our
case, INR increased just after the introduction of ropinirole.
Moreover, no other circumstances contributing to cerebral
haemorrhage were found (blood pressure was carefully
checked by her referring doctor before the intracranial hem-
orrhage and was always noted as normal, no serotoninergic
reuptake inhibitors, antiaggregant, or spironolactone were
used). According to the French method, the causal relation-
ship assessment score for drug interaction was I3 for fluin-
dione, estimated as ‘‘likely,’’ and I2 for ropinirole, estimated
as ‘‘plausible.’’5 Other dopamine agonists such as pramip-
exole or rotigotine do not inhibit CYP1A2 at doses used in
clinical practice, so interactions with vitamin K antagonists
are not expected for these drugs.
Parkinson’s disease affects 1%–2% of the population at
65 years old, 3.4% at 75 years old, and 4% at 85 years
old.6 In the developed world, 1%–2% of the population
receives vitamin K antagonists,7 with the incidence of atrial
fibrillation the main indication for vitamin K antagonists,
also increasing with age. For 10,000 persons in the general
population, around 4 are likely to be treated with vitamin K

FIG. 1. International normalized ratio (INR) in the 6 months preceding
patient’s arrival to hospital, with the therapeutic range (INR between 2
and 3) and the actual doses of fluindione and ropinirole.
antagonists and to present with Parkinson’s disease. Consi-
dering the widespread use of both vitamin K antagonists and
ropinirole for the treatment of Parkinson’s disease, 2 hypo-
theses can be drawn from the finding that only 1 case report
of vitamin K antagonist (warfarin) overdose related to ropi-
nirole interaction has been previously published: the rela-
tively rare occurrence of this drug interaction or its
underreporting. The present observation could suggest that
INR monitoring should be intensified when ropinirole (and
possibly other antiparkinsonian drugs interacting with
CYP1A2) is associated with fluindione in order to avoid a
serious and preventable adverse effect.
Julia Grossac, MD,1 Stéphanie Ruiz, MD,1
Emmanuelle Bondon-Guitton, PharmD,2
Franck-Emmanuel Roux, MD, PhD,3
Olivier Fourcade, MD, PhD,1
Jean-Louis Montastruc, MD, PhD,2 and
Thomas Geeraerts, MD, PhD1*
1 tional rehabilitation, in PD patients, with autonomy in daily
Pôle Anesthésie Réanimation, Equipe d’accueil
‘‘modélisation de l’agression tissulaire et
nociceptive,’’ Université Paul Sabatier et Institut
Fédératif de Recherche 150, Hôpital Purpan,
Centre Hospitalier Universitaire de Toulouse,
Toulouse, France; 2Service de Pharmacologie
Clinique, Centre Midi-Pyrénées de
Pharmacovigilance, de Pharmacoépidémiologie et
d’Informations sur le Médicament, Unité de
Pharmacoépidémiologie de l’INSERM U 1027,
Centre Hospitalier Universitaire de Toulouse,
Toulouse, France; and 3Service de Neurochirurgie–
INSERM 825, Hôpital Purpan, Centre Hospitalier
Universitaire de Toulouse, Toulouse, France
References
1. Huttner HB, Juttler E, Hug A, Kohrmann M, Schellinger PD,
Steiner T. Intracerebral hemorrhage related to anticoagulant ther-
apy. Nervenarzt 2006;77:671–672, 674–676, 678–681.
2. Bair JD, Oppelt TF. Warfarin and ropinirole interaction. Ann
Pharmacother 2001;35:1202–1204.
3. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes
involved in the 7-hydroxylation of R- and S-warfarin enantiomers.
Biochem Pharmacol 1997;54:1195–1203.
L E T T E R S : N E W O B S E R V A T I O N S
4. Bloomer JC, Clarke SE, Chenery RJ. In vitro identification of the
P450 enzymes responsible for the metabolism of ropinirole. Drug
Metab Dispos 1997;25:840–844.
5. Begaud B, Evreux JC, Jouglard J, Lagier G. Imputation of the
unexpected or toxic effects of drugs. Actualization of the method
used in France. Therapie 1985;40:111–118.
6. Calne DB. Treatment of Parkinson’s disease. N Engl J Med 1993;
329:1021–1027.
7. Schulman S. Unresolved issues in anticoagulant therapy. J Thromb
Haemost 2003;1:1464–1470.
Action Observation Treatment
Improves Autonomy in Daily Activities
in Parkinson’s Disease Patients:
Results from a Pilot Study
Physical therapy is considered a necessary complement to
pharmacological treatment in Parkinson’s disease (PD) patients.
It is usually restricted to specific motor skills (eg, gait) and is
effective for a short period, and the effects of trained tasks
do not tend to be generalized in patients’ environment.1
Therefore, there is a pressing need for rehabilitation programs
with a strong neurophysiological basis aimed at the training
of meaningful tasks, such as daily life activities.
The systematic observation of daily actions followed by
their imitation (Action Observation Treatment; AOT) is a
novel rehabilitation approach exploiting a well-known neu-
rophysiological mechanism matching an observed action on
its motor counterpart.2 So far, AOT has been successfully
applied to the rehabilitation of chronic stroke patients,3,4
lower limb functions in postsurgical orthopedic patients,5
and walking ability in PD patients with freezing of gait.6
The aim of the present pilot randomized controlled trial was
to assess the benefits of this approach, in addition to conven-
activities as the main treatment target. All PD patients con-
secutively admitted in our department from January 2009 to
January 2010 were eligible for the study. Inclusion criteria
were age between 18 and 75 years, normal or corrected to
normal visual and auditory acuity, Mini–Mental State Exam-
ination score 24, and absence of depression. A group of 15
patients was enrolled and randomly assigned either to a case
(n ¼ 7) or a control (n ¼ 8) group. Disease severity was
assessed according to the Hoehn and Yahr (HY) Scale.7
Both groups underwent conventional physiotherapy. In addi-
tion, patients in the case group were asked to observe, and
subsequently execute, different daily actions presented
through video clips (AOT). Controls observed video clips
with no motor content and subsequently performed the
------------------------------------------------------------
*Correspondence to: Giovanni Buccino, Department of Medical
Sciences, University Magna Graecia, Catanzaro, Italy; buccino@unicz.it
Funding agencies: This study was supported by an FIL grant (to G.B.).
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 5 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23745
Movement Disorders, Vol. 26, No. 10, 2011 1963
L E T T E R S : N E W O B S E R V A T I O N S
Table 1. Demographic and median and interquartile
range of clinical and functional data of participants
at baseline
Case group (n ¼ 7) Control group (n ¼ 8)
Sex (M/F) 5/2 5/3
Age (y) 68 (59–80) 73.5 (67.5–76.5)
Duration of disease (y) 7 (5–19) 9 (5.5–13.5)
H&Y 3 (2.5–4) 1.7 (1.5–2.3)
UPDRS 54 (44–74) 42 (30.7–60.7)
FIM 112 (91–113) 108 (101–115)
same actions as cases. Functional evaluation was carried out
by a physician blinded to group assignment before and after
rehabilitation treatment, using scales measuring autonomy in
daily activities (Unified Parkinson’s Disease Rating scale,
UPDRS, and Functional Independence Measure, FIM).8,9
Scores on the UPDRS and FIM were the primary outcome
measures. Patients were always tested in the ‘‘on’’ phase. In
both groups the ongoing drug treatment was not modified
for the duration of the rehabilitation program.
Demographic data and clinical and functional findings
from all participants at baseline are reported in Table 1. All
patients suffered from idiopathic PD according to the
Parkinson’s Disease Society Brain Bank criteria.
Cases and controls did not differ at baseline, except for
disease severity as assessed by the HY Scale, for which cases
were worse than controls (P ¼ .009). Both groups improved
after treatment, but functional score gain (D) was higher in
cases than in controls on both the UPDRS (P ¼ .004) and
the FIM (P ¼ .002). The Spearman test showed no correla-
tion between disease severity, as assessed by the HY Scale
at baseline and D values at outcome (UPDRS: r ¼ 0.530,
P ¼ .051; FIM: r ¼ 0.351, P ¼ .20).
These preliminary findings suggest that AOT may improve
autonomy in daily activities in PD patients, thus representing
a promising rehabilitative tool in PD patients.
Giovanni Buccino, MD, PhD, 1* Roberto Gatti, PT,2
Maria C. Giusti, MD,2 Anna Negrotti, MD,3
Alice Rossi, PT, 2 Stefano Calzetti, MD,3
and Stefano F. Cappa, MD2
1 his way home and was found 10 hours later. The patient’s
Department of Medical Sciences, University
Magna Graecia, Catanzaro, Italy;
2
Department of Clinical Neuroscience, San
Raffaele Scientific Institute and Vita Salute
University, Milan, Italy; and
3
Department of Neuroscience, Section of
Neurology, University of Parma, Parma, Italy
References
1. Kwakkel G, De Goede CJT, van Wegen EEH. Impact of physical
therapy for Parkinson’s disease: a critical review of the literature.
Parkinsonism Relat Disord 2007;13:478–487.
2. Buccino G, Solodkin A, Small SL. Functions of the mirror neuron
system: implications for neurorehabilitation. Cogn Behav Neurol
2006;19:55–63.
3. Ertelt D, Small S, Solodkin A, et al. Action observation has a posi-
tive impact on rehabilitation of motor deficits after stroke. Neuro-
image 2007;36 Suppl 2:164–173.
1964 Movement Disorders, Vol. 26, No. 10, 2011
4. Franceschini M, Agosti M, Cantagallo A, Sale P, Mancuso M, Buc-
cino G. Mirror neurons: action observation treatment as a tool in
stroke rehabilitation. Eur J Phys Rehab Med 2010;46:517–523.
5. Bellelli G, Buccino G, Bernardini B, Padovani A, Trabucchi M.
Action observation treatment improves recovery of postsurgical
P
orthopedic patients: evidence for a top-down effect? Arch Phys
Med Rehabil 2010;91:1489–1494.
6. Pelosin E, Avanzino A, Bove M, Stramesi P, Nieuwboer A,
.463
Abbruzzese G. Action observation improves freezing of gait in
.995 patients with Parkinson’s disease. Neurorehab Neural Repair
.009 2010;24:746–752.
.121 7. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortal-
.613 ity. Neurology 1967;17:427–442.
8. Van Hilten J, van der Zwan A, Zwinderman A, Roos R. Rating
impairment and disability in Parkinson’s disease: evaluation of the
Unified Parkinson’s Disease Rating Scale. Mov Disord 1994;9:84–88.
9. Keith RA, Granger CV, Hamilton BB, Sherwin FS. The functional
independence measure: a new tool for rehabilitation. Adv Clin
Rehabil 1987;1:6–18.
Progressive Supranuclear Palsy-Like
Phenotype Caused by Progranulin
p.Thr272fs Mutation
In 2002, a 68-year-old man visited our clinic complain-
ing of early memory disturbances. Following assessment, a
diagnosis of multiple-domain mild cognitive impairment
(MCI) associated with chronic cerebrovascular disease was
made. Past medical history included diabetes, arterial hyper-
tension, bilateral internal carotid artery stenosis (30%), and
previous prostatic cancer (negative follow-up). Family history
included early-onset dementia (mother, at age 59). One year
later, episodic memory and functional autonomy further deter-
iorated (MMSE: 23), and the patient was diagnosed with mild
possible Alzheimer’s disease and prescribed donepezil. A brain
MR scan in 2004 demonstrated initial enlargement of the perime-
sencephalic cisterns (normal in 2002), coupled with chronic
ischemic damage and ventricular enlargement. No evidence of
movement dysfunction was detected, which suggested the partial
expression of a more widespread atrophy-determining pathology.
In 2005, the patient’s younger sister (age 69 years) gradually
developed severe dysarthria and MCI. Meantime, the cognitive
profile of our patient remained stable, although in 2006 he lost
MMSE score was 19, and he was given memantine as an add-on
therapy. Mild agitation emerged but was promptly attenuated
following haloperidol administration (0.5 mg twice a day). A few
months later the patient stopped demonstrating behavioral dis-
turbances, and haloperidol was discontinued. Initial bradykine-
sia, rigidity, and instability were reported. In 2009, the patient
presented with buccofacial dyskinesias, which was tentatively
interpreted as a consequence of the previous neuroleptic
------------------------------------------------------------
*Correspondence to: Lucio Tremolizzo, Department of Neuroscience
and Biomedical Technologies, University of Milano-Bicocca, Monza,
Italy; lucio.tremolizzo@unimib.it
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 3 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23749

FIG. 1. Proband brain MR scan. T1W sagittal section (A) and T1W axial section (B) showing midbrain atrophy highly suggestive of PSP, coupled
with severe ventricular and sulcal enlargement. Substantial brain atrophy with corresponding thinning of the corpus callosum is evident. Both the
‘‘hummingbird’’ sign (A) and the ‘‘Mickey mouse’’ sign (B) are present.
exposure. Hyperkinesia spontaneously ameliorated, but the
patient gradually became dysphagic. At further follow-up he pre-
sented with clear supranuclear ophthalmoplegia, dysphagia, dys-
arthria, dysphonia, and an akinetic-rigid picture with
camptocormic posture, shuffling gait, and a tendency to fall back-
ward. A diagnosis of possible progressive supranuclear palsy
(PSP) was made according to NINDS-SPSP criteria1 which was
compatible with the brain MR scan (Fig. 1). The sister of the
patient was concomitantly diagnosed with PSP at another center.
Progranulin (PGRN) and tau mutation tests were performed:
tau was negative, whereas the PGRN test demonstrated a heter-
ozygous c.813_816delCACT (p.Thr272SerfsX23) mutation
within exon 7 of the gene, a common mutation in northern
Italy.2 Genetic tests performed on the affected sister showed an
identical positive result.
Progranulin mutations lead to a loss-of-function tau-nega-
tive pathology, which is generally clinically expressed within
the FTLD and CBD spectrum.3 Conversely, PSP has a distinc-
tive neuropathological phenotype that is specifically related to
the group of tauopathies, particularly to the mutation of the
MAPT gene (FTDP-17). Asymmetric parkinsonism may be
associated with PGRN mutations, often developing a picture
of tau-negative CBD, although the term FTDP-17 (PGRN)
has come into use.4 PGRN mutations are known to lead to
particular variations in phenotype because they may deter-
mine, for example, Alzheimer’s disease phenotypes, amyotro-
phic lateral sclerosis, or rapidly progressive dementia often
evolving to a secondary diagnosis (mostly CBD) within 2
years.5 The single clinical phenotype never described before in
association to PGRN is PSP. In fact, PGRN mutations have
not previously been reported in clinically diagnosed PSP,6 and
PSP is still regarded as a disease with a generally univocal cor-
respondence between clinical and pathological diagnosis, that
is, tauopathy. Interestingly, predominant frontal behavioral
and cognitive changes, often resulting in an incorrect initial di-
agnosis of frontotemporal dementia, have been described in
about 20% of PSP cases.7 Anyway, we suggest that a more
comprehensive definition of our case might be ‘‘PSP-like,’’
describing a clinical mimic of this tauopathy expressing a tau-
L E T T E R S : N E W O B S E R V A T I O N S
negative pathology. Only 1 previous report indicates similar-
ities to our case: a PGRN mutation carrier with an unusual
clinical presentation characterized by the co-occurrence of pro-
gressive dysarthria, oculomotor abnormalities and buccofacial
dyskinesias.8 However, the authors excluded PSP on clinical
grounds, and neuroimaging showed no significant atrophy.
Pathological changes were noted in the basal ganglia including
patchy gliosis, but no overt neuronal loss was detected. TDP-
43-positive inclusions in the striatum and cortex were also
reported. Brain stem nuclei examination was negative for both
neuronal loss or gliosis and neurofibrillary tangles or Lewy
bodies. Interestingly, a PSP-like clinical phenotype and a com-
patible tau neuropathology have been recently described by
the same authors in a single patient carrying an LRRK2 muta-
tion, a gene previously associated with synuclein pathology.9
Together, this evidence suggests that more genes may be
involved in determining PSP phenotypes. Further genetic testing
may be necessary in familial PSP cases where tau mutations are
absent, particularly if atypical clinical features are present.
Moreover, the novel association reported here further expands
the clinical borders encompassed by PGRN mutations.
Lucio Tremolizzo, MD, PhD,1,2* Francesca Bertola, PhD,3
Giorgio Casati, PhD,3 Alberto Piperno, MD,3
Carlo Ferrarese, MD, PhD,1,2
and Ildebrando Appollonio, MD1,2
1
Department of Neurology, S. Gerardo Hospital,
Monza, Italy; 2Department of Neuroscience and
Biomedical Technologies, University of
Milano-Bicocca, Monza, Italy; and 3Consortium
of Human Molecular Genetics, University of
Milano-Bicocca, Monza, Italy
References
1. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the
diagnosis of progressive supranuclear palsy (Steele-Richardson-
Movement Disorders, Vol. 26, No. 10, 2011 1965
L E T T E R S : N E W O B S E R V A T I O N S
Olszewski syndrome): report of the NINDS-SPSP international
workshop. Neurology 1996;47:1–9.
2. Tremolizzo L, Gelosa G, Galbussera A, et al. Higher than expected
progranulin mutation rate in a case series of Italian FTLD patients.
Alzheimer Dis Assoc Disord 2009;23:301.
3. Kertesz A. Clinical features and diagnosis of frontotemporal de-
mentia. Front Neurol Neurosci 2009;24:140–148.
4. Boeve BF, Hutton M. Refining frontotemporal dementia with
parkinsonism linked to chromosome 17: introducing FTDP-17
(MAPT) and FTDP-17 (PGRN). Arch Neurol 2008;65:
460–464.
5. Moreno F, Indakoetxea B, Barandiaran M, et al. ‘‘Frontotemporo-
parietal’’ dementia: clinical phenotype associated with the c.709–
1G>A PGRN mutation. Neurology 2009;73:1367–1374.
6. Borroni B, Archetti S, Alberici A, et al. Progranulin genetic variations
in frontotemporal lobar degeneration: evidence for low mutation fre-
quency in an Italian clinical series. Neurogenetics 2008;9:197–205.
7. Donker Kaat L, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden
HJ, van Swieten JC. Frontal presentation in progressive supranu-
clear palsy. Neurology 2007;69:723–729.
8. Wider C, Uitti RJ, Wszolek ZK, et al. Progranulin gene mutation
with an unusual clinical and neuropathologic presentation. Mov
Disord 2008;23:1168–1173.
9. Wider C, Dickson DW, Wszolek ZK. Leucine-rich repeat kinase 2
gene-associated disease: redefining genotype-phenotype correlation.
Neurodegener Dis 2010;7:175–179.
Has ‘‘Levodopa-Induced Neuropathy’’
Been Reported in Parkinson’s Disease
Clinical Trials?
An association between levodopa and the occurrence of
peripheral neuropathy in Parkinson’s disease (PD) patients
has been proposed by Toth et al1,2 and is supported by case
reports of neuropathy in patients treated with Duodopa.3–5
These reports led to a safety alert concerning the effects of
levodopa on the peripheral nervous system.
To quantify the frequency with which neuropathy is
reported as an adverse effect in PD trials, we conducted a
systematic review of randomized parallel-design trials that
compared marketed antiparkinsonian drugs with placebo.
Our search included eligible trials that were published before
December 2009. The primary outcome from our study was
the frequency with which neuropathy, polyneuropathy, or
mononeuropathy was reported as an adverse event. The sec-
ondary outcomes were clinical signs or symptoms possibly
related to neuropathy and reported as an adverse event.
From a total of 795 identified studies, 79 satisfied the
selection criteria and were included in our analysis. These
studies involved 10,620 patients treated with antiparkinso-
nian agents and 6710 patients treated with placebo.
------------------------------------------------------------
*Correspondence to: Joaquim J. Ferreira, Neurological Clinical
Research Unit, Instituto de Medicina Molecular, Lisbon School of
Medicine, Lisbon, Portugal; joaquimjferreira@net.sapo.pt
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 12 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23760
1966 Movement Disorders, Vol. 26, No. 10, 2011
Interestingly, we did not find any reports of neuropathy as
an adverse event in studies involving levodopa (or any other
antiparkinsonian drug) in either the drug- or placebo-treated
subjects. We also found that the frequency of adverse events
suggestive of neuropathy did not differ significantly between
the treated and placebo groups in any of the included trials.
Although only 1 trial provided a direct comparison between
levodopa and placebo,6 a total of 12,543 patients in the
selected trials were exposed to levodopa while taking other
adjuvant therapeutic compounds.
In a recent case–control study, Toth et al2 reported a higher
frequency of polyneuropathy in PD patients (55%) than in
age- and sex-matched subjects from the general population
(9%). The mean age of the PD patients with neuropathy was
72.1 years compared with 63.2 years for those without neu-
ropathy. It is known that clinical trials tend to enroll younger
and healthier patients, and this might have contributed to the
absence of neuropathy reports in PD studies.
Only 7 of the included studies contained follow-up data
beyond 52 weeks, and it is possible that levodopa can cause
neuropathy after more prolonged exposure. An eventual
pathogenic effect of levodopa therapy might also depend on
the route of administration. Unfortunately, we did not find
any parallel-group, placebo-controlled trials with Duodopa.
It is generally accepted that clinical trials are not well
designed for evaluating drug safety and that investigators fre-
quently overlook mild or unexpected adverse events such as
neuropathy in PD. However, our results do allow us to con-
clude that a diagnosis of neuropathy is rare in the context of
clinical trials. In cases where neuropathy is being overlooked,
at minimum one should assume that severe manifestations are
absent. These conclusions cannot be extrapolated for sub-
groups of patients who are usually excluded from clinical tri-
als, for example, patients with severe or prolonged disease,
significant comorbidity, or advanced age.
In conclusion, the safety data from PD clinical trials do
not support an association between antiparkinsonian drugs
and the development of neuropathy.
Tiago Teodoro, MD, Daniela Pires, MD,
Mário M. Rosa, MD, Miguel Coelho, MD,
Cristina Sampaio, MD, PhD, and
Joaquim J. Ferreira, MD, PhD*
Neurological Clinical Research Unit, Instituto de
Medicina Molecular, Lisbon School of Medicine,
Lisbon, Portugal
References
1. Toth C, Brown MS, Furtado S, Suchowersky O, Zochodne D.
Neuropathy as a potential complication of levodopa use in Parkin-
son’s disease. Mov Disord 2008;23:1850–1859.
2. Toth C, Breithaupt K, Suchowersky O, et al. Levodopa, methylma-
lonic acid, and neuropathy in idiopathic Parkinson disease. Ann
Neurol 2010;68:28–36.
3. Manca D, Cossu G, Murgia D, et al. Reversible encephalopathy
and axonal neuropathy in Parkinson’s disease during duodopa
therapy. Mov Disord 2009;24:2293–2294.
4. Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion
for advanced Parkinson’s disease: 12-month treatment outcome.
Mov Disord 2007;22:1145–1149.

5. Urban P, Wellach I, Weis J, et al. Subacute axonal neuropathy in
Parkinson’s Disease with cobalamine and vitamin B6 deficiency
under duodopa therapy. Mov Disord 2010;25:1748–1752.
6. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression
of Parkinson’s disease. N Engl J Med 2004;351:2498–2508.
Relationship Between Sleep and
Dysautonomic Symptoms Assessed
by Self-Report Scales
Sleep disturbances and autonomic dysfunction have
been implicated in Parkinson’s disease (PD) since the first
descriptions of this condition.1 A possible relationship
between dysautonomia and sleep disorders is suggested by
the anatomical proximity of their regulatory centers in the
brain stem.2
The objective of this study was to explore the clinical
relationship between self-reported autonomic and sleep
dysfunction.
Patients and Methods
This was a cross-sectional study including a total of 60
patients, all diagnosed with PD3 and recruited consecutively
on attendance at a movement disorders clinic. Informed con-
sent was required before enrollment. All patients underwent
a complete neurological examination including completion
of the Unified Parkinson Disease Rating Scale (UPDRS). Au-
tonomic dysfunction was assessed with the SCOPA-AUT
scale,4 and sleep dysfunction was assessed using the Parkin-
son’s Disease Sleep Scale (PDSS) and Epworth Daytime
Sleepiness Scale (Epworth).
Statistical Analysis
Means and standard deviations were determined for the
quantitative variables. Stepwise regression analyses were per-
formed to identify variables predictive of sleep disorders in
PD patients.
The SPSS-12 package for Windows (SPSS Inc., Chicago
IL) was used for the statistical analysis.
Results
The mean SCOPA-AUT total score was 20.9 6 12.1, and
urinary was the most affected domain (28.4 6 21.6). The
mean PDSS total score was 113 6 16.3. The total score on
the SCOPA-AUT was found to be weakly correlated with
------------------------------------------------------------
*Correspondence to: Juan Carlos Gómez-Esteban, Movement
Disorders Unit, Neurology Department, Hospital de Cruces,
Baracaldo, Vizcaya, Spain; juancarlos.gomezesteban@gmail.com
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online
version of this article.
Published online 12 May 2011 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.23761
L E T T E R S : N E W O B S E R V A T I O N S
age and disease duration (0.29, P ¼ .025; and 0.29, P ¼
.028, respectively) and to be moderately correlated with
UPDRS III score (0.44, P < .001).
We also detected some correlation between scores on the
different scales, namely, between the SCOPA-AUT and
PDSS ( 0.60, P < .001) and between SCOPA-AUT and
Epworth (0.36, P ¼ .007). The domains of SCOPA-AUT
that showed the highest correlation with the PDSS total
score were the gastrointestinal and urinary domains (Table
1). On the other hand, when grouping the PDSS items,5
‘‘nocturnal motor symptoms’’ (items 10–13) and ‘‘nocturia’’
(items 8 and 9) both showed a moderate correlation with
total SCOPA-AUT score (Table 1).
After introducing the variables into a stepwise linear
regression model using PDSS as the dependent variable, we
found that SCOPA-AUT alone accounted for 27.3% of the
variance in the PDSS (F ¼ 21046; P < .001).
Discussion
This study demonstrates that autonomic symptoms
assessed by the SCOPA-AUT scale are strongly related to
nocturnal sleep problems in PD patients. A previous study
also showed a similar relationship.6 Four domains were
found to be significantly correlated with the PDSS total
score: the gastrointestinal, urinary, pupilomotor, and ther-
moregulatory domains. The result for the urinary domain
comes as no surprise, as nocturnal urinary symptoms directly
influence the quality of sleep.
This is the first study exploring the relationship between
sleep and autonomic nervous system disorders using self-
reported scales. It illustrates high rates of autonomic symp-
toms and sleep disturbance in PD and confirms a strong cor-
relation between the 2 types of problems. The anatomical
proximity and concomitant degeneration of sleep and auto-
nomic regulatory centers in the brain stem could explain this
correlation. However, this may well be a simplification of a
much more complex relationship, and further research is
required.
Beatriz Tijero, MD,1 Johanne Somme, MD,1
Juan Carlos Gómez-Esteban, MD, PhD,1*
Koldo Berganzo, MD,1 Ishan Adhikari, MD,2
Elena Lezcano, MD, PhD,1 Iker Bilbao, MD,1
Iñigo Garamendi, MD,1 and Juan José Zarranz, MD, PhD1
1
Movement Disorders Unit, Neurology
Department, Hospital de Cruces, Baracaldo,
Vizcaya, Spain; and 2Dysautonomia Center,
Langone Medical Center, New York University,
New York, New York, USA
References
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Braak E. Staging of brain pathology related to sporadic Parkinson’s
disease. Neurobiol Aging. 2003;24:197–211.
Movement Disorders, Vol. 26, No. 10, 2011 1967
L E T T E R S : N E W O B S E R V A T I O N S

Table 1. Correlation coefficients (Spearman’s rho) between scores on the PDSS scale and its dimensions and scores
on the SCOPA AUT scale and dimensions

SCOPA AUT Gastrointestinal Urinary Cardiovascular Thermoregulatory Pupil Sexual

a a a a b
PDSS 0.60 0.49 0.49 0.21 0.38 0.30 0.23
 Quality 0.12 0.01 0.01 0.13 0.13 0.07 0.20
 Insomnia 0.23 0.18 0.18 0.16 0.07 0.02 0.13
 Restlessness 0.27b 0.11 0.21 0.09 0.30b 0.16 0.11
 Psychosis 0.37a 0.39a 0.23 0.11 0.30 0.23 0.01
 Nocturia 0.53a 0.29b 0.63a 0.13 0.24 0.26b 0.25
 Motor 0.53a 0.47a 0.29b 0.36a 0.30b 0.34a 0.21
 Refreshment 0.35a 0.30b 0.30b 0.12 0.19 0.16 0.08
 Dozing 0.47a 0.48a 0.29b 0.11 0.34b 0.10 0.16

PDSS, Parkinson’s Disease Sleep Scale (PDSS items were grouped according Chaudhuri’s recommendations).4
a
P < .001; bP < .01.

3. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diag-
nosis of Lewy body Parkinson’s disease. Neurology. 2001;57:
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scale: a new instrument for assessing sleep and nocturnal disability in
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6. Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout
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1968 Movement Disorders, Vol. 26, No. 10, 2011