Relationship Between Sleep and Dysautono

LETTERS: NEW O B S E RVAT I O N S
Acoustic Assessment of Voice and The extracted speech parameters were assessed using
measures of phonation [VT1] including jitter, shimmer,
Speech Disorders in Parkinson’s noise-to-harmonics ratio (NHR), and harmonics-to-noise
Disease Through Quick Vocal Test ratio (HNR)5; respiration [VT2] including sound pressure
level decline (SPLD)4; articulation [VT2] including robust
formant periodicity correlation (RFPC), and spectral distance
The disorders of voice and speech in Parkinson’s disease change variation (SDCV)4; and prosody [VT3] including
(PD) result from involvements in several subsystems includ- voice fundamental frequency variations (F0 SD).6 Supporting
ing respiration, phonation, articulation, and prosody.1–3 Information Table 1 details the measurements used.
We investigated the feasibility of acoustic measures for the For every subject, average values (speech performances)
identification of voice and speech disorders in PD, using a for each acoustic measurement were calculated. Two-sided
quick vocal test consisting of sustained phonation, diadocho- Wilcoxon rank-sum and Spearman rank tests were per-
kinetic task, and running speech. Various traditional and formed to find differences between groups and within-group
novel acoustic measurements have been designed in order to correlations. Subsequently, an exhaustive search of all possi-
be gender independent, represent all speech subsystems, ble measure combinations was performed, and a predictive
reduce the time required for voice investigation, and provide model was built using a kernel support vector machine
a reliable automated assessment in practice.4 (SVM) to find the best combination of measurements to dif-
ferentiate PD from HC subjects. Cross-validation with the
Patients and Methods leave-one-out method was used to validate reproducibility of
A total of 46 Czech native participants were recruited. the SVM classifier.7
Twenty-four of them fulfilled the diagnostic criteria for PD
and were examined before the symptomatic treatment was Results
started: 20 men, 4 women; mean age (6 SD), 60.9 6 11.2 In total, 116 vocal recordings were collected and used for
years; duration of PD symptoms, 31.3 6 22.3 months (range,
classification. Significant differences between the 2 groups
6–84 months); H&Y stage, 2.2 6 0.5 (range, 1–3); and
were found in all 8 measurements. In addition, from all per-
UPDRS motor score, 17.4 6 7.1 (range, 5–32); with UPDRS
formed correlations, statistically significant relationships
speech item ¼ 0 in 13 patients and speech item ¼ 1 in 11
were found between several measures of articulation and
patients. As a healthy control (HC) group, 22 persons with no
phonation and subscores of bradykinesia and rigidity (Sup-
history of neurological or communication disorders were
porting Table 2). The best classification performance of
included: 15 men, 7 women; mean age, 58.7 6 14.6 years. Age
85.0% 6 6.1% was reached in a combination of 4 measures
distribution did not differ significantly between the groups.
Each participant was instructed to perform 3 vocal tasks: that represent all PD-related affected speech subsystems,
[VT1], sustained phonation at a comfortable pitch and loud- including the impaired ability to maintain sound pressure
ness as constant and long as possible, at least 5 seconds on 1 level (SPLD), increased noise components during phonation
breath; [VT2], diadochokinetic (DDK) task requiring rapid, (NHR), lowered accuracy of articulation (RFPC), and
steady /pa/-/ta/-/ka/ syllable repetition as constant and long reduced melody of speech (F0 SD); see Figure 1. The maxi-
as possible, repeated at least 5 times on 1 breath; and mal classification accuracy using simple task was 81.3% 6
[VT3], running speech for approximately 80 seconds. For 6.9% for running speech, 75.6% 6 8.3% for sustained pho-
reproducibility of data, each task was repeated at least 2 nation, and 71.4% 6 8.3% for DDK task; therefore,
times for every subject. 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-
*Correspondence to: Evžen Růžička, Department of Neurology,
Charles University in Prague, First Faculty of Medicine and General gated the potential of using acoustic analysis in detecting voice
University Hospital in Prague, Katerinska 30, Praha 2, Czech Republic; and speech disorders in PD. The method demonstrated that it
[email protected]
can accurately differentiate PD patients from HCs. This could
Relevant conflicts of interest/financial disclosures: Nothing to report. be of high clinical relevance as subtle abnormalities such as
The study was partly supported by the Czech Science Foundation,
project GACR 102/08/H008, Czech Ministry of Health, project NT
reduced melody in running speech were detectable from the
11331-6/2010, Grant Agency of the Czech Technical University in early stage of PD. Admittedly, the study has certain limita-
Prague, project SGS 10/180/OHK3/2T/13, and Czech Ministry of tions. Although the uneven gender representation of patients
Education, projects MSM 0021620849, MSM 6840770012, and MSM and controls could be offset by gender independence of
0021620806.
Full financial disclosures and author roles may be found in the online designed acoustic measurement methods, our sample size
version of this article. remains rather small. Should our results be confirmed on a
Published online 11 April 2011 in Wiley Online Library larger population sample, voice and speech disorders might be
(wileyonlinelibrary.com). DOI: 10.1002/mds.23680 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 6. Boril H, Pollak P. Direct time domain fundamental estimation of
speech in noisy conditions. In: EUSIPCO Proceedings, Vienna, Aus-
expected advent of neuroprotective treatment. In a more tria; 2004.
modest scope, the use of automated acoustic vocal tests
7. Franc V, Hlavac V. Statistical pattern recognition toolbox for Mat-
can ease the clinical monitoring of voice and speech disorders lab. Prague, Czech Republic: Czech Technical University, Faculty
progression as well as the effects of medication on speech pro- of Electrical Engineering, Center for Machine Perception; 2004.
duction and can serve as feedback in voice treatment. Available at http://cmp.felk.cvut.cz/. Accessed January 15, 2011.
Jan Rusz, MSc,1,2,3 Roman Čmejla, MSc, PhD,1

Hana Růžičková, MSc,3 Jiřı́ Klempı́ř, MD, PhD,3 THAP1 Mutations Are Infrequent in
Veronika Majerová, MD,3 Jana Picmausová, MD,3 Spasmodic Dysphonia
Jan Roth, MD, PhD,3 and Evžen Růžička, MD, DSc3*
1
Czech Technical University in Prague, Faculty of Spasmodic dysphonia (SD, laryngeal dystonia) is a rela-
Electrical Engineering, Department of Circuit tively rare focal form of dystonia with an estimated preva-
Theory, Prague, Czech Republic; 2Charles lence of 1 per 23,500.1 In SD the voice is affected as a result
University in Prague, First Faculty of Medicine, of involuntary movements of 1 or more muscles of the lar-
Department of Pathophysiology, Prague, Czech ynx during speech.2 Mutations in THAP1 (OMIM 609520)
Republic; and 3Charles University in Prague, First cause DYT6 dystonia.3 DYT6 dystonia patients typically
Faculty of Medicine, Department of Neurology have prominent laryngeal and oromandibular involvement,
and Centre of Clinical Neuroscience, Prague, causing speech difficulties, a rare feature in other familial
Czech Republic 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
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 *Correspondence to: Marina A.J. Tijssen, Department of Neurology,
speech I: Speech characteristics and L-dopa therapy. Neurorehab Academic Medical Center, University of Amsterdam, Amsterdam, The
2002;17:237–246. Netherlands; [email protected]
3. Skodda S, Schlegel U. Speech rate and rhythm in Parkinson’s dis- Relevant conflicts of interest/financial disclosures: Justus L Groen
ease. Mov Disord 2008;23:985–992. received an AMC Graduate School Scholarship. Katja Ritz and Marina
4. Rusz J, Cmejla R, Ruzickova H, Ruzicka E. Quantitative acoustic A.J. Tijssen received research support from the Prinses Beatrix Fund.
measurements for characterization of voice and speech disorders in Full financial disclosures and author roles may be found in the online
early untreated Parkinson’s disease. J Acoust Soc Am 2011;129: version of this article.
350–367. This study was supported by the Prinses Beatrix Fund.
5. Boersma P, Weenink D. Praat, a system for doing phonetics by Published online 29 April 2011 in Wiley Online Library
computer. Glot Int 2001;5:341–345. (wileyonlinelibrary.com). DOI: 10.1002/mds.23682
1952 Movement Disorders, Vol. 26, No. 10, 2011

Table 1. Characteristics of SD patients included in 1 patient carried a new variant in intron 1, c.71þ18C>T,
THAP1 screening not found in the control population. This variant was not
predicted to affect splicing. We did not find a significant dif-
Number of patients 109
ference in frequency of any of these variants; however, sam-
Female 67%
Mean AaO (SD, range) 45.6 (15.3, 7–87)
ple size was small, making data pooling of homogeneous
Mean AaE (SD) 58.2 (14.0) patient groups warranted. These variants are candidates for
Positive family history 16%a future association studies.
Early onset (age < 26 y) 16%a Xiao et al5 previously screened 460 American SD patients
Segmental dystonia 18% and found 2 nonsynonymous genetic variants (0.43%) with
Spread to neck 10% late-onset SD in nonfamilial cases.5 This low prevalence of
Spread to oromandibular region 6% THAP1 genetic variation in SD dystonia patients is compa-
Blepharospasm 1%
rable with other focal and segmental dystonia groups.5–7 In
Writer’s cramp 1%
contrast, THAP1 mutations are causal for up to 25% of
familial cases with generalized dystonia with prominent la-
All patients are of Dutch ancestry.
a
Half of the familial SD patients had an early age at onset. SD, standard ryngeal involvement.4
deviation; AaO, age at onset; AaE, age at examination. Most mutations causing early-onset DYT6 were found in
the DNA-binding THAP domain.7 In the 2 previously
90% of mutation carriers show segmental or generalized described focal SD patients,5 mutations were in the coiled coil
dystonia.3,4 Mutation screening of THAP1 in focal and seg- domain of THAP1. In this domain, additional rare synony-
mental dystonia patient groups showed a mutation fre- mous variants were found in a control subject and in 2 focal
quency below 1%.5–7 Some focal SD patients (with or cervical dystonia patients.7 These observations might indicate
without a positive family history) were found to carry non- a less pathogenic role of mutations affecting this region. The
synonymous THAP1 mutations.4,5 Ser51Gly change identified here affects an amino acid highly
Here, we studied the frequency of THAP1 mutations in a conserved from man to chicken (Homologene: 10005; http://
consecutive cohort of focal and segmental SD patients www.ncbi.nlm.nih.gov/homologene) in the THAP domain.
attending the botulinum toxin treatment outpatient clinic. Our screening of Dutch SD patients attending the botuli-
The study was approved by the local ethics committees of num toxin treatment clinic confirms that mutations in the
participating centers. After giving informed consent, DYT6 gene THAP1 are present but rare in focal and seg-
patients were included in a clinical database, and blood mental SD patients.
was drawn.
A total of 109 SD patients of Dutch ancestry were Justus L. Groen, MD,1,2 Eren Yildirim, MSs,1
included in this genetic screening study (Table 1). The 3 cod- Katja Ritz, MSc,2 Frank Baas, MD, PhD,1
ing exons of THAP1 were sequenced in all patients and 185 Jacobus J. van Hilten, MD, PhD,3
controls (Caucasians from the Dutch Blood Bank), including Freerk W. van der Meulen, MD, PhD,4
the 50 untranslated region (UTR) and 500 bp of the 30 UTR Ton P. Langeveld, MD, PhD,5
(ABI 3730 capillary system; Applied Biosystems, Carlsbad, and Marina A.J. Tijssen, MD, PhD1*
CA). To exclude possible mutations at splice sites, at least
50 base pairs of the upstream and downstream intronic
Departments of 1Neurology and 2Neurogenetics,
sequences that flank each exon were sequenced. Sequences
Academic Medical Center, University of
were analyzed using CodonCode software (Dedham, MA;
Amsterdam, Amsterdam, The Netherlands;
reference sequence: NM_018105.2) and Alamut 1.5 Interac- 3
Department of Neurology, Leiden University
tive Biosoftware (Rouen, France).
Medical Centre, Leiden, The Netherlands;
Of the 109 screened SD patients, including 89 focal and 4
Department of Otorhinolaryngology—Head and
20 segmental SD patients, 1 patient (0.9%) carried a hetero-
Neck Surgery, Academic Medical Center,
zygous missense mutation, c.151A>G (p.Ser51Gly), in exon
University of Amsterdam, Amsterdam,
2 of THAP1. This patient was a 35-year-old woman who
The Netherlands; and
had SD since age 14 years that spread to the oromandibular 5
Department of Otorhinolaryngology—Head and
region starting at age 21. At examination we saw a patient
Neck Surgery, Leiden University Medical Center,
with segmental dystonia affecting the tongue and laryngeal
Leiden, The Netherlands
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 References
involuntary tongue movements. Family history was negative 1. Butler AG, Duffey PO, Hawthorne MR, Barnes MP. An epide-
miologic survey of dystonia within the entire population of
for dystonia. We encountered 4 additional sequence variants northeast England over the past nine years. Adv Neurol 2004;
in the 50 UTR and intronic regions of THAP1: c.-237_- 94:95–99.
236GA>TT had a frequency of 4.5% in SD cases and 2.2% 2. Blitzer A. Spasmodic dysphonia and botulinum toxin: experience
in the control group (P ¼ .22); c.71þ9C>A was present in from the largest treatment series. Eur J Neurol 2010;17(Suppl 1):
28–30.
0.5% of the control group but was not found in the patient
3. Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the
group; c.71þ126T>C (rs71521601) had a frequency of THAP1 gene are responsible for DYT6 primary torsion dystonia.
5.5% in patients and 3.8% in controls (P ¼ .49); and Nat Genet 2009;41:286–288.

4. Bressman SB, Raymond D, Fuchs T, Heiman GA, Ozelius LJ, ing and action tremor and moderate akinetic-rigid symptoms
Saunders-Pullman R. Mutations in THAP1 (DYT6) in early-onset
dystonia: a genetic screening study. Lancet Neurol 2009;8: of the left hemibody. The tremor frequency of 5–6 Hz and
441–446. the lack of an intention tremor or other cerebellar symptoms
5. Xiao J, Zhao Y, Bastian RW, et al. Novel THAP1 sequence var- were not compatible with the diagnosis of Holmes tremor,
iants in primary dystonia. Neurology 2010;74:229–238. and despite the slightly irregular and atypical tremor presen-
6. Djarmati A, Schneider SA, Lohmann K, et al. Mutations in tation (Video), a diagnosis of a secondary, tremor-dominant
THAP1 (DYT6) and generalised dystonia with prominent spas-
modic dysphonia: a genetic screening study. Lancet Neurol 2009;8: hemiparkinsonism was made. Repeated, high-resolution MRI
447–452. did not reveal any structural abnormality at the level of the
7. Groen JL, Ritz K, Contarino MF, et al. DYT6 dystonia: Mutation midbrain, basal ganglia, or thalamus after the initial insult or
screening, phenotype, and response to deep brain stimulation. Mov during the subsequent course. A FDG-PET of brain glucose
Disord 2010;25:2420–2427.
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-
Successful Deep Brain Stimulation bamazepine, valproic acid, propranolol, bornaprine, and clo-
zapine failed. From a combined dopaminergic treatment with
in a Case of Posttraumatic Tremor L-dopa/benserazide (up to 900 mg daily) and cabergoline (3
and Hemiparkinsonism 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-
Holmes tremor is the most common clinical presentation score, 8) in the off state, which did not change after a chal-
of posttraumatic tremor caused by a midbrain lesion. It is lenge with 200 mg of levodopa/benserazide.
defined as a slow-frequency (<4.5 Hz), irregular resting and Although the ventrointermediate (VIM) thalamic nucleus
intention tremor with a variable onset of weeks to months af- is considered the standard surgical target for posttraumatic
ter the initial insult.1 The co-occurrence of parkinsonian and tremors,2 in this case we also planned for functional map-
cerebellar features reflects the combined lesioning of nigrostri- ping of the subthalamic nucleus (STN) because of the iso-
atal and cerebellothalamic pathways in this condition. Here, lated Parkinsonian syndrome. Surgical implantation of deep
we describe the clinical course of a patient with posttraumatic brain electrodes following our published procedure3,4 took
tremor presenting as tremor-dominant hemiparkinsonism,
place on May 26, 2005, after the patient had given informed
which resulted from an isolated lesion of the nigrostriatal
consent to this individual therapeutic trial. Intraoperative
pathway several weeks after a single closed-head injury.
high-frequency stimulation of the dorsolateral STN as identi-
The 31-year-old man slipped in his bathroom and sus-
fied by microrecordings resulted in a marked reduction of
tained a severe head trauma with a left hemisphere subdural
contralateral rigidity, bradykinesia, and rest tremor, whereas
hemorrhage requiring surgical evacuation. He recovered from
kinetic tremor persisted. VIM stimulation reduced tremor
an incomplete palsy of the left third cranial nerve and a slight
but did not alleviate bradykinesia and rigidity. Therefore, it
left-sided hemiparesis without neurological sequelae. Approx-
was decided to implant permanent electrodes (model 3389,
imately 2 months later, he gradually developed a violent rest-
Medtronic Inc., Minneapolis, MN) into both targets, which
were subsequently connected to a single pulse generator
------------------------------------------------------------ (Kinetra, Medtronic Inc., Minneapolis, MN).
Additional Supporting Information may be found in the online version of Postoperatively, resting tremor as well as akinetic-rigid
this article. symptoms showed an immediate response to monopolar
Current address for Marcus O. Pinsker: Department of Functional and STN-HFS with low current amplitudes. Kinetic tremor was
Stereotactic Neurosurgery, University of Freiburg, Germany. absent for several weeks after surgery, probably because of a
Current address for Jens Volkmann: Department of Neurology, Julius- microlesioning effect, but a gradual return, which could not
Maximilians-University, Würzburg, Germany. be treated by reprogramming of STN-HFS, necessitated addi-
*Correspondence to: Jens Volkmann, Department of Neurology, tional monopolar stimulation of the VIM. The patient discon-
Julius-Maximilians-University, Würzburg, Germany; tinued all oral medication and experienced a stable treatment
[email protected]
response of combined neurostimulation for the subsequent 3
Relevant conflicts of interest/financial disclosures: René Reese, years without any adverse effects. Because of an infection of
Daniela Falk, and Marcus O. Pinsker received speaking honoraria from
Medtronic. Georg Ebersbach received honoraria for presentations and the stimulation system, the patient had to be explanted 5
advisory board activities from Boehringer Ingelheim Pharma, years after initial implantation. Parkinsonian symptoms rap-
Cephalon, Desitin Pharma, GlaxoSmithKline, Valeant, Novartis, Orion, idly worsened to the preoperative state. Six months later, the
and Schwarz Pharma (UCB). H. Maximilian Mehdorn received
speaking honoraria and consultant fees from Medtronic. Günther stimulation system was reimplanted, and the patient achieved
Deuschl received grant support for conducting a multicenter study. the former symptom relief (STN: Cþ2 ;2.6 V;60 ls/130 Hz;
Jens Volkmann received honoraria for lectures, consulting fees, and VIM: Cþ5 ;1.5 V;90 ls/130 Hz). Clinical evaluation 1 week
grant support from Medtronic Inc.
Full financial disclosures and author roles may be found in the online after second implantation resulted in the following UPDRS
version of this article. scores: STNoff/VIMoff—motor score, 25 (tremor score, 8);
Published online 29 April 2011 in Wiley Online Library STNon/VIM off—motor score, 12 (tremor score, 3); STNon/
(wileyonlinelibrary.com). DOI: 10.1002/mds.23686 VIMon—motor score, 8 (tremor score, 0).

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
FIG. 1. 123-I-FP-CIT SPECT superimposed on patient’s preoperative intention tremor. Brain 2007;130:1608–1625.
cranial MRI demonstrates the virtually complete cessation of striatal
dopamine transporter binding in the right brain hemisphere. 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.
Our case demonstrates, that combined neurostimulation 6. Zijlmans J, Booij J, Valk J, Lees A, Horstink M. Posttraumatic tremor
of the VIM and STN can be successful in treating posttrau- without parkinsonism in a patient with complete contralateral loss of
the nigrostriatal pathway. Mov Disord 2002;17:1086–1088.
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
Lack of Association of the UCHL-1
VIM stimulation reduced intention tremor, but suppression Gene with Parkinson’s Disease in a
of resting tremor required additional STN-HFS.5 Our case, Greek Cohort: A Haplotype-Tagging
however, is unique because of the lack of any macroscopic
brain lesion on MRI and the dopaminergic striatal denerva- Approach
tion proven by SPECT, which most probably resulted from
an isolated axonal shearing trauma of the nigrostriatal path- Ubiquitin carboxy-terminal hydrolase L1 (UCHL-1) is an
way. Zijlmans et al6 described a similar patient with a abundant neuron-specific deubiquitinating enzyme in the
tremor syndrome resulting from a complete striatal dopami- human brain that is essential for the cellular clearance of
nergic denervation after a traumatic substantia nigra hemor- abnormal proteins.1
rhage. Interestingly, this patient had no akinetic-rigid The amino acid substitution of serine to tyrosine (S18Y)
symptoms, probably because of the hemorrhagic lesion in the UCHL-1 gene has been found to modify enzymatic
extending into the STN, and the tremor responded well to a activity and to be associated with neurodegenerative
subsequent thalamotomy.
------------------------------------------------------------
Legends to the Video *Correspondence to: Georgios M. Hadjigeorgiou, [email protected]
Video Segment 1. STNoff/VIMoff—the patient presents Relevant conflicts of interest/financial disclosures: Nothing to report.
with a tremor-dominant left hemibody parkinsonian syn- This work was supported in part through the Research Committee of
the University of Thessaly (Code: 2845), Institute of Biomedical
drome without any sign of cerebellar dysfunction 1 week af- Research & Technology, CERETETH (Code: 01-04-207), and PENED
ter second implantation of the stimulation system. 03 grant 650, ‘‘Genetic Variations of PD Associated Genes in the
Video Segment 2. STNon/VIMoff—bradykinesia and rigid- Greek Population and their Functional Analysis,’’ from the Hellenic
ity are markedly reduced, but alternating movements are still Secretariat of Research and Technology (to D.V. and L.S.). Novartis
Hellas was a cosponsor of this grant.
impaired by a kinetic tremor. Full financial disclosures and author roles may be found in the online
Video Segment 3. STNon/VIMon—additional VIM stimu- version of this article.
lation virtually stops tremor and now allows the patient to Published online 28 May 2011 in Wiley Online Library
perform smooth alternating hand movements. (wileyonlinelibrary.com). DOI: 10.1002/mds.23694

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

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

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

supports the observation that the distinct components of

Holmes’ tremor can manifest in the complete absence of cerebel-
Palatal Tremor Visualized by
lar input. Cine MRI
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 Palatal tremor is a rhythmic involuntary movement of the
reported to have resolved the residual resting and postural trem- soft palate caused by lesions within the Guillain-Mollaret tri-
ors. Unlike our case, however, the patient was reported to have angle, which comprises the red nucleus, inferior olive, and
shown no obvious signs of discrete brain injury. dentate nucleus.1 Symptomatic forms of palatal tremor can
Taken together, these reports support the notion that (1) the result from cerebrovascular disease, trauma, neuroinflamma-
human central nervous system is capable of producing resting, tion, malignoma, or neurodegeneration including progressive
postural, and intention tremor rhythms in the complete ab- ataxia and palatal tremor syndrome and may also be associ-
sence of unilateral cerebellar input, (2) disruption to the cere- ated with GFAP gene mutations causing Alexander’s dis-
bellothalamic pathway appears necessary for the manifestation ease.2 In contrast to essential forms of palatal tremor, in
of Holmes’ tremor, and (3) localized neural intervention ameli- secondary forms, ear clicks may be absent, and adjacent
orates differential aspects of Holmes’ tremor, suggesting that muscles can also be affected, causing combinations of oculo-
disruption to the nigrostriatal and cerebellothalamic pathways pharyngeal-laryngeal-palatal tremor. ENT assessment may
produces selective alteration in tremor manifestation. 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-
John-Stuart Brittain, PhD,1* Ned Jenkinson, PhD,2 charges. Recent developments in morphological neuroimaging
Peter Holland, BA,2 Raed A. Joundi, BSc,1 techniques enable more accurate demonstration of the under-
Alex L. Green, MD,1,2 and Tipu Z. Aziz, DMedSci2 lying structural alterations of brain parenchymal lesions. Fur-
thermore, very fast MRI sequences, for example, 2D FLASH
1
Department of Physiology, Anatomy & Genetics, (Fast Low Angle SHot), offer the capability of exceeding
University of Oxford, Oxford, United Kingdom; purely morphological imaging, also depicting dynamic struc-
2
Functional Neurosurgery and Experimental tural displacements such as tissue movement. Originally, this
Neurology, Nuffield Department of Surgical Sciences, novel technique was developed for cardiac imaging and has
University of Oxford, Oxford, United Kingdom 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-
References tal tremor. Our patient, a 72-year old man with a medical his-
1. Bittar RG, Hyam J, Nandi D, et al. Thalamotomy versus thalamic tory of hypertension, hyperlipoproteinemia, and nicotine
stimulation for multiple sclerosis tremor. J Clin Neurosci 2005;12:
638–642. abuse, presented with sudden onset of dysarthria, dysphagia,
2. Deuschl G, Bain P, Brin M, Ad Hoc Scientific Committee.Consen-
and gait difficulties. After a few days, he also developed invol-
sus statement of the Movement Disorders Society on tremor. Mov untary rhythmic movements of the soft palate. Ear clicks were
Disord 1998;13:2–23. absent. There was, however, synchronous involvement of ad-
3. Bain PG, Findley LJ, Atchison P, et al. Assessing tremor severity. jacent pharyngeal, laryngeal, and facial muscles and extraocu-
J Neurol Neurosurg Psychiatry 1993;56:868–873. lar muscles (see Video 1). Applying a balanced turbo field
4. Deuschl G, Wilms H, Krack P, Wurker M, Heiss W-D.Function of echo (BTFE) cine MRI sequence (slice thickness, 9 mm; TR,
the cerebellum in parkinsonian rest tremor and Holmes’ tremor.
Ann Neurol 1999;46:126–128. 2.1 ms; TE, 1.0 ms; flip angle, 40 ; FOV, 320 384; in-plane
5. Raethjen J, Deuschl G. Tremor. Curr Opin Neurol 2009;22: resolution, 1.2 1.2 mm2), we could demonstrate the dynam-
400–405. ics of these complex movements (see Video 2). A routine MRI
6. Romanelli P, Bronte-Stewart H, Courtney T, Heit G.Possible neces- workup revealed ischemic lesions affecting the Guillain-Mol-
sity for deep brain stimulation of both the ventralis intermedius laret triangle, presenting as signal hyperintensity on T2-
and subthalamic nuclei to resolve Holmes’ tremor. J Neurosurg
2003;99:566–571. 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;
[email protected]
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

reconstruction, permitting the acquisition of real-time MRI at a 9. Algin O, Hakyemez B, Parlak M. The efficiency of PC-MRI in di-
agnosis of normal pressure hydrocephalus and prediction of shunt
temporal resolution of 20–30 ms at very high spatial resolution response. Acad Radiol 2010;17:181–187.
(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-
Fragile X–Associated Tremor
ment disorders such as laryngeal and pharyngeal movement Ataxia Syndrome sine Tremor
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. 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
Legends to the Video 50–200 CGG repeats is associated with fragile X tremor-
Video 1. On clinical examination, full view shows rhyth- ataxia syndrome (FXTAS), characterized by cerebellar ataxia
mic movements of the larynx and ocular movements with and tremor, with parkinsonism and cognitive deficits. The
nystagmus to the right, affecting both eyes. On intraoral condition, however, is rare on FMR1 screening of cohorts of
assessment, there is palatal tremor. Video endoscopy shows idiopathic ataxia, tremor, or parkinsonism.1,2 FXTAS is
laryngeal involvement. more common in males, whereas female premutation carriers
Video 2. Balanced turbo field echo (BTFE) cine MRI (40-sec- more commonly manifest with premature menopause and
ond cycle; 1.3 Hz/slice) demonstrates the dynamics of rhythmic ovarian failure, occurring in 16%.3,4
pharyngeal and laryngeal contractions because of the pharyn- The MRI finding of increased T2 signal change in the
geal-laryngeal-palatal tremor. Inferior olive hypertrophy, often middle cerebellar peduncles (MCPs) can be found in 82%
associated with palatal tremor, was not evident in this case. A of FXTAS. These MRI findings, although useful in the di-
time stamp conveys the time scale of the movements. agnosis of the tremulous FXTAS patient, are less discrimi-
natory in predominately ataxic individuals, with MCP change
Jens T. Wuerfel, MD,1 Guenter Seidel, MD,2 reported in multiple system atrophy, spinocerebellar ataxia
Uwe Melchert, PhD,1 Andreas Sprenger, PhD,2 (SCA), and dentatorubro-pallidoluysian atrophy.5 Tremor,
Cathrin Hansmann, MD,2 Peter Trillenberg, MD,2 although a major clinical feature of FXTAS, can be absent in
Dirk Petersen, MD,1 Rainer Schoenweiler, MD,3 and 20%.6 The absence in an individual FXTAS subject to both
Susanne A. Schneider, MD, PhD2* tremor and typical signal change in the MCP is uncommon
1
and presents a considerable challenge.
Institute of Neuroradiology and 2Department of Here we present 2 cases of FXTAS sine tremor—1 case
Neurology, University Luebeck, Luebeck, had typical MCP signal change, the other lacked this diag-
Germany; and 3Department of Phoniatrics and nostic radiological feature. Both cases were confirmed FMR1
Pediatric Audiology (Speech, Language, Voice, premutation carriers on subsequent genetic testing. There
Swallowing, and Hearing Disorders), was no family history of fragile X syndrome in either case.
University Clinic of Schleswig-Holstein, Case 1 was a 57-year-old man with 4 years of progres-
Campus Luebeck, Germany sive incoordination, dysarthria, falls, and recent memory
decline.
References Examination revealed upper limb dysdiadochokinesia
1. Deuschl G, Toro C, Valls-Sole J, et al. Symptomatic and essential and dysmetria. There was no rest, postural, or kinetic
palatal tremor. 1. Clinical, physiological and MRI analysis. Brain tremor. Eye movements showed hypometric saccades with
1994;117:775–788.
gaze-evoked horizontal nystagmus. There was impaired
2. Samuel M, Torun N, Tuite PJ, et al. Progressive ataxia and palatal
tremor (PAPT): clinical and MRI assessment with review of palatal
verbal memory and working memory, but normal executive
tremors. Brain 2004;127:1252–1268. function, visual memory, and visuospatial performance. The
3. Finke C, Jumah MDJT, Ploner CJ. An endoscopic view of sympto- patient was examined over a 2-year period, and there was
matic palatal tremor. Neurology 2010;74:e16. never any indication of tremor (see video clip 1).
4. Zhang S, Block KT, Frahm J. Magnetic resonance imaging in real The patient’s brother, of a similar age, had also experi-
time: Advances using radial FLASH. J Magn Reson Imaging 2010; enced balance difficulty. On direct questioning, there was
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
------------------------------------------------------------
*Correspondence to: Nin Bajaj, Department of Neurology, Queens
myocardial function and perfusion after myocardial infarct. Rofo Medical Centre, Nottingham, United Kingdom; [email protected]
1997;167:399–405.
7. Penn RD, Linninger A. The physics of hydrocephalus. Pediatr Neu- Relevant conflicts of interest/financial disclosures: Nothing to report.
rosurg 2009;45:161–174. Full financial disclosures and author roles may be found in the online
8. Sweetman B, Xenos M, Zitella L, et al. Three-dimensional compu-
tational prediction of cerebrospinal fluid flow in the human brain. Published online 31 May 2011 in Wiley Online Library
Comput Biol Med 2011;41:67–75. (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 logical criterion of minor MRI lesions involving cerebral
among the patient’s female relatives, leading to menopause white matter with moderate to severe generalized brain atro-
in the third or fourth decade of life. This, together with the phy. Both cases lacked the major clinical criterion of tremor,
MCP sign on MRI, prompted testing for FXTAS. and this led to the diagnosis of FXTAS being overlooked
Case 2 was a 67-year-old man who gave a history of 2 initially.
years of leg fatigue on walking, progressive unsteadiness, These cases highlight several important lessons. First, cases
and 1 year of memory decline. of FXTAS can be mimics of idiopathic late-onset cerebellar
Eye movements were normal. There was no rest, postural, ataxia with absence of tremor. Second, the MRI scan may not
or kinetic tremor. There was mild bradykinesia of alternat- be helpful. Third, a positive history of premature ovarian fail-
ing movements of the left hand, dysdiadochokinesia of the ure in female relatives should be sought and genetic testing of
left hand more than the right, and unsteadiness on heel–toe at risk individuals offered with appropriate counseling about
walking. Gait was broad-based, and pull test showed abnor- fertility and the future risk of having children with fragile X
mal postural reflexes (video clip 2). syndrome. Thus, unless the diagnosis of FXTAS is actively con-
Cognitive testing showed moderate reduction in verbal sidered and tested for genetically, it might be missed.
memory and working memory, mild reduction in visual
memory, mild visuospatial abnormality, and normal execu-
tive function. Legends to the Video
Thyroid function, full blood count, autoimmune screen,
paraneoplastic screen, and celiac serology were negative or Video—Case 1. Fatiguable decrement of repetitive finger
normal. Genetic testing for SCA-1, -2, -3, -6, -7, -12, and - taps left hand. Dysmetria and dysdiachokinesia bilaterally.
17 and Friedreich’s ataxia was negative. CSF examination Broad-based gait and heel–toe ataxia.
and nerve conduction/electromyography in case 1 were
normal. Video—Case 2. Hyperpronation of outstretched hand.
A 123I-/V-cu-fluoro-propyl-2b-carbomethoxy-3b-(4-iodo- Irregularity of repetitive movements left arm. Left-sided dys-
phenyl) nortropane ([123I] FP-CIT) SPECT of the brain was diadochokinesia. Broad-based ataxic gait.
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 Nin Bajaj, PhD,1* Derek Soon, MRCP,1 and
imaging in case 2 showed marked cortical and midbrain at- Niall Quinn, MD2
rophy. No MCP high signal was seen (Fig. 1D).
Southern analysis of the FMR1 gene revealed an unmethy- 1
Department of Neurology, Queens Medical
lated CGG expansion of 100 repeats in case 1 and 87 unme- Centre, Nottingham, United Kingdom; and 2Sobell
thylated CGG repeats in case 2, confirming FXTAS (normal, Department of Motor Neuroscience and
<50 repeats; intermediate, 50–58 repeats; premutation, 59– Movement Disorders, Institute of Neurology,
200 [unmethylated] repeats; full mutation, >200 methylated London, United Kingdom
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
References
1. Reis AH, Ferreira AC, Gomes KB, et al. Frequency of FMR1 pre-
FXTAS according to current clinical criteria, with 1 major mutation in individuals with ataxia and/or tremor and/or parkin-
clinical criterion of cerebellar gait ataxia and 1 minor radio- sonism. Genet Mol Res 2008;7:74–84.

2. Kamm C, Healy DG, Quinn NP, et al. European Multiple System department, the Glasgow coma score was 3. Cerebral CT
Atrophy Study Group. The fragile X tremor ataxia syndrome in
the differential diagnosis of multiple system atrophy: data from the
scan showed an important hematoma in the right cerebellar
EMSA Study Group. Brain 2005;128:1855–1860. hemisphere with intraventricular hemorrhage. The INR was
3. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, 4, the platelet count 178 G/L, and the partial prothrombin
parkinsonism, and generalized brain atrophy in male carriers of time 31/31 seconds. An emergency reversal of vitamin K
fragile X. Neurology 2001;57:127–130.
antagonists was performed with intravenous prothrombin
4. Berry-Kravis E, Abrams L, Coffey SM, et al. Fragile X-associated complex concentrates (20 IU/kg) and vitamin K (10 mg).
tremor/ataxia syndrome: clinical features, genetics, and testing
guidelines. Mov Disord 2007;22:2018–2030. The INR decreased to 1.1. Ventricular drainage was then
5. Brunberg JA, Jacquemont S, Hagerman RJ, et al. Fragile X premu- rapidly performed. After speaking to the patient’s family, no
tation carriers: characteristic MR imaging findings of adult male recent changes in diet or habits were identified.
patients with progressive cerebellar and cognitive dysfunction. Afterward, parkinsonism was still observed. Use of ropi-
AJNR Am J Neuroradiol 2002;23:1757–1766.
nirole was definitively stopped, and neurologist consultants
6. Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premuta-
tion tremor/ataxia syndrome:molecular, clinical, and neuroimaging replaced it with L-dopa. Fluindione was also stopped, and
correlates. Am J Hum Genet 2003;72:869–878. 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
Severe Intracranial Bleeding Related performed 4 months after intracranial bleeding found no evi-
to Vitamin K Antagonist-Ropinirole dence of vascular abnormality.
Interaction Discussion
Intracranial hemorrhage is a life-threatening adverse reac-
Bleeding is an adverse effect of vitamin K antagonists. The tion of vitamin K antagonist use and is associated with a
risk of bleeding is increased if vitamin K antagonists is asso- high mortality rate. Anticoagulant drugs increase the risk of
ciated with drugs that could increase the chances of hemor- intracranial hemorrhage by 7, with a direct relationship with
rhagic events such as aspirin, nonsteroidal anti-inflammatory the INR level.1
drugs, or heparin. Dopamine agonists are not reported to INR is known to be very labile with diet modification,
increase the risk of bleeding related to vitamin K antago- and vitamin K antagonists are known to have several inter-
nists. Here we describe a case of severe intracranial hemor- actions with other drugs. Our patient did not have any
rhage related to an interaction between fluindione and recent diet modification and was only exposed to fluindione
ropinirole, a dopamine agonist used in the treatment of and ropinirole. A case of INR increase without bleeding
Parkinson’s disease. complications after the administration of ropinirole in a
A 64-year-old woman was admitted to our neurointensive patient receiving warfarin has been reported.2 To our knowl-
care unit for intracranial hemorrhage in the right cerebellar edge, our case is the first to describe a major adverse drug
hemisphere. Her previous medical history included recently reaction (intracranial bleeding) due to overdose of vitamin K
diagnosed Parkinson’s disease and multiple thrombophlebitis antagonists related to ropinirole interaction. Vitamin K
with no known etiology. The patient had been prescribed an antagonists are hydroxylated and reduced by cytochrome
oral anticoagulant (fluindione) for 10 years, since a second P450.3 The R-enantiomer is metabolized by cytochrome
episode of thrombophlebitis. The international normalized ra- CYP1A2. Ropinirole is also metabolised by CYP1A2.4 Thus,
tio (INR) was checked twice a year over the 10-year period. ropinirole–fluindione competition can occur, with the accu-
The INR values were very stable within the therapeutic range mulation of R-enantiomers of vitamin K antagonists. In our
(between 2 and 3). She never consulted for hemorrhage. case, INR increased just after the introduction of ropinirole.
Two months before admission to the intensive care unit, Moreover, no other circumstances contributing to cerebral
the patient was prescribed ropinirole in progressively haemorrhage were found (blood pressure was carefully
increasing doses (6 mg per day during the first month and 8 checked by her referring doctor before the intracranial hem-
mg per day thereafter), in order to treat parkinsonism with orrhage and was always noted as normal, no serotoninergic
important tremor. One month after the introduction of the reuptake inhibitors, antiaggregant, or spironolactone were
ropinirole, the INR was 3.2, and as a consequence, the dos- used). According to the French method, the causal relation-
age of fluindione was halved (Fig. 1). One month later, the ship assessment score for drug interaction was I3 for fluin-
patient suddenly presented the following symptoms: vomit- dione, estimated as ‘‘likely,’’ and I2 for ropinirole, estimated
ing, headache, and a progressively decreasing level of con- as ‘‘plausible.’’5 Other dopamine agonists such as pramip-
sciousness. When the patient was admitted to the emergency
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
*Correspondence to: Thomas Geeraerts, Coordination d’Anesthésie,
Hôpital Purpan, Toulouse, France; [email protected] 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
Full financial disclosures and author roles may be found in the online receives vitamin K antagonists,7 with the incidence of atrial
version of this article. fibrillation the main indication for vitamin K antagonists,
Published online 25 April 2011 in Wiley Online Library also increasing with age. For 10,000 persons in the general
(wileyonlinelibrary.com). DOI: 10.1002/mds.23733 population, around 4 are likely to be treated with vitamin K

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
FIG. 1. International normalized ratio (INR) in the 6 months preceding
patient’s arrival to hospital, with the therapeutic range (INR between 2
in Parkinson’s Disease Patients:
and 3) and the actual doses of fluindione and ropinirole. Results from a Pilot Study
antagonists and to present with Parkinson’s disease. Consi-
dering the widespread use of both vitamin K antagonists and
Physical therapy is considered a necessary complement to
ropinirole for the treatment of Parkinson’s disease, 2 hypo-
pharmacological treatment in Parkinson’s disease (PD) patients.
theses can be drawn from the finding that only 1 case report
It is usually restricted to specific motor skills (eg, gait) and is
of vitamin K antagonist (warfarin) overdose related to ropi-
effective for a short period, and the effects of trained tasks
nirole interaction has been previously published: the rela-
do not tend to be generalized in patients’ environment.1
tively rare occurrence of this drug interaction or its
Therefore, there is a pressing need for rehabilitation programs
underreporting. The present observation could suggest that
with a strong neurophysiological basis aimed at the training
INR monitoring should be intensified when ropinirole (and
of meaningful tasks, such as daily life activities.
possibly other antiparkinsonian drugs interacting with
The systematic observation of daily actions followed by
CYP1A2) is associated with fluindione in order to avoid a
their imitation (Action Observation Treatment; AOT) is a
serious and preventable adverse effect.
novel rehabilitation approach exploiting a well-known neu-
Julia Grossac, MD,1 Stéphanie Ruiz, MD,1 rophysiological mechanism matching an observed action on
Emmanuelle Bondon-Guitton, PharmD,2 its motor counterpart.2 So far, AOT has been successfully
Franck-Emmanuel Roux, MD, PhD,3 applied to the rehabilitation of chronic stroke patients,3,4
Olivier Fourcade, MD, PhD,1 lower limb functions in postsurgical orthopedic patients,5
Jean-Louis Montastruc, MD, PhD,2 and and walking ability in PD patients with freezing of gait.6
Thomas Geeraerts, MD, PhD1* The aim of the present pilot randomized controlled trial was
to assess the benefits of this approach, in addition to conven-
1 tional rehabilitation, in PD patients, with autonomy in daily
Pôle Anesthésie Réanimation, Equipe d’accueil
activities as the main treatment target. All PD patients con-
‘‘modélisation de l’agression tissulaire et
secutively admitted in our department from January 2009 to
nociceptive,’’ Université Paul Sabatier et Institut
January 2010 were eligible for the study. Inclusion criteria
Fédératif de Recherche 150, Hôpital Purpan,
were age between 18 and 75 years, normal or corrected to
Centre Hospitalier Universitaire de Toulouse,
normal visual and auditory acuity, Mini–Mental State Exam-
Toulouse, France; 2Service de Pharmacologie
ination score 24, and absence of depression. A group of 15
Clinique, Centre Midi-Pyrénées de
patients was enrolled and randomly assigned either to a case
Pharmacovigilance, de Pharmacoépidémiologie et
(n ¼ 7) or a control (n ¼ 8) group. Disease severity was
d’Informations sur le Médicament, Unité de
assessed according to the Hoehn and Yahr (HY) Scale.7
Pharmacoépidémiologie de l’INSERM U 1027,
Both groups underwent conventional physiotherapy. In addi-
Centre Hospitalier Universitaire de Toulouse,
tion, patients in the case group were asked to observe, and
Toulouse, France; and 3Service de Neurochirurgie–
subsequently execute, different daily actions presented
INSERM 825, Hôpital Purpan, Centre Hospitalier
through video clips (AOT). Controls observed video clips
Universitaire de Toulouse, Toulouse, France
with no motor content and subsequently performed the
References ------------------------------------------------------------
*Correspondence to: Giovanni Buccino, Department of Medical
1. Huttner HB, Juttler E, Hug A, Kohrmann M, Schellinger PD, Sciences, University Magna Graecia, Catanzaro, Italy; [email protected]
Steiner T. Intracerebral hemorrhage related to anticoagulant ther-
apy. Nervenarzt 2006;77:671–672, 674–676, 678–681. Funding agencies: This study was supported by an FIL grant (to G.B.).
2. Bair JD, Oppelt TF. Warfarin and ropinirole interaction. Ann Relevant conflicts of interest/financial disclosures: Nothing to report.
Pharmacother 2001;35:1202–1204. Full financial disclosures and author roles may be found in the online
3. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes
involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Published online 5 May 2011 in Wiley Online Library
Biochem Pharmacol 1997;54:1195–1203. (wileyonlinelibrary.com). DOI: 10.1002/mds.23745

Table 1. Demographic and median and interquartile 4. Franceschini M, Agosti M, Cantagallo A, Sale P, Mancuso M, Buc-
cino G. Mirror neurons: action observation treatment as a tool in
range of clinical and functional data of participants stroke rehabilitation. Eur J Phys Rehab Med 2010;46:517–523.
at baseline 5. Bellelli G, Buccino G, Bernardini B, Padovani A, Trabucchi M.
Action observation treatment improves recovery of postsurgical
Case group (n ¼ 7) Control group (n ¼ 8) P
orthopedic patients: evidence for a top-down effect? Arch Phys
Med Rehabil 2010;91:1489–1494.
Sex (M/F) 5/2 5/3
6. Pelosin E, Avanzino A, Bove M, Stramesi P, Nieuwboer A,
Age (y) 68 (59–80) 73.5 (67.5–76.5) .463
Abbruzzese G. Action observation improves freezing of gait in
Duration of disease (y) 7 (5–19) 9 (5.5–13.5) .995 patients with Parkinson’s disease. Neurorehab Neural Repair
H&Y 3 (2.5–4) 1.7 (1.5–2.3) .009 2010;24:746–752.
UPDRS 54 (44–74) 42 (30.7–60.7) .121 7. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortal-
FIM 112 (91–113) 108 (101–115) .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
same actions as cases. Functional evaluation was carried out Unified Parkinson’s Disease Rating Scale. Mov Disord 1994;9:84–88.
by a physician blinded to group assignment before and after 9. Keith RA, Granger CV, Hamilton BB, Sherwin FS. The functional
rehabilitation treatment, using scales measuring autonomy in independence measure: a new tool for rehabilitation. Adv Clin
daily activities (Unified Parkinson’s Disease Rating scale, Rehabil 1987;1:6–18.
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 Progressive Supranuclear Palsy-Like
for the duration of the rehabilitation program. Phenotype Caused by Progranulin
Demographic data and clinical and functional findings
from all participants at baseline are reported in Table 1. All
p.Thr272fs Mutation
patients suffered from idiopathic PD according to the
Parkinson’s Disease Society Brain Bank criteria. In 2002, a 68-year-old man visited our clinic complain-
Cases and controls did not differ at baseline, except for ing of early memory disturbances. Following assessment, a
disease severity as assessed by the HY Scale, for which cases diagnosis of multiple-domain mild cognitive impairment
were worse than controls (P ¼ .009). Both groups improved (MCI) associated with chronic cerebrovascular disease was
after treatment, but functional score gain (D) was higher in made. Past medical history included diabetes, arterial hyper-
cases than in controls on both the UPDRS (P ¼ .004) and tension, bilateral internal carotid artery stenosis (30%), and
the FIM (P ¼ .002). The Spearman test showed no correla- previous prostatic cancer (negative follow-up). Family history
tion between disease severity, as assessed by the HY Scale included early-onset dementia (mother, at age 59). One year
at baseline and D values at outcome (UPDRS: r ¼ 0.530, later, episodic memory and functional autonomy further deter-
P ¼ .051; FIM: r ¼ 0.351, P ¼ .20). iorated (MMSE: 23), and the patient was diagnosed with mild
These preliminary findings suggest that AOT may improve possible Alzheimer’s disease and prescribed donepezil. A brain
autonomy in daily activities in PD patients, thus representing MR scan in 2004 demonstrated initial enlargement of the perime-
a promising rehabilitative tool in PD patients. sencephalic cisterns (normal in 2002), coupled with chronic
ischemic damage and ventricular enlargement. No evidence of
movement dysfunction was detected, which suggested the partial
Giovanni Buccino, MD, PhD, 1* Roberto Gatti, PT,2
expression of a more widespread atrophy-determining pathology.
Maria C. Giusti, MD,2 Anna Negrotti, MD,3
In 2005, the patient’s younger sister (age 69 years) gradually
Alice Rossi, PT, 2 Stefano Calzetti, MD,3
developed severe dysarthria and MCI. Meantime, the cognitive
and Stefano F. Cappa, MD2
profile of our patient remained stable, although in 2006 he lost
1 his way home and was found 10 hours later. The patient’s
Department of Medical Sciences, University MMSE score was 19, and he was given memantine as an add-on
Magna Graecia, Catanzaro, Italy; therapy. Mild agitation emerged but was promptly attenuated
2
Department of Clinical Neuroscience, San following haloperidol administration (0.5 mg twice a day). A few
Raffaele Scientific Institute and Vita Salute months later the patient stopped demonstrating behavioral dis-
University, Milan, Italy; and turbances, and haloperidol was discontinued. Initial bradykine-
3
Department of Neuroscience, Section of sia, rigidity, and instability were reported. In 2009, the patient
Neurology, University of Parma, Parma, Italy presented with buccofacial dyskinesias, which was tentatively
interpreted as a consequence of the previous neuroleptic
References ------------------------------------------------------------
1. Kwakkel G, De Goede CJT, van Wegen EEH. Impact of physical *Correspondence to: Lucio Tremolizzo, Department of Neuroscience
therapy for Parkinson’s disease: a critical review of the literature. and Biomedical Technologies, University of Milano-Bicocca, Monza,
Parkinsonism Relat Disord 2007;13:478–487. Italy; [email protected]
2. Buccino G, Solodkin A, Small SL. Functions of the mirror neuron
system: implications for neurorehabilitation. Cogn Behav Neurol Relevant conflicts of interest/financial disclosures: Nothing to report.
2006;19:55–63. Full financial disclosures and author roles may be found in the online
3. Ertelt D, Small S, Solodkin A, et al. Action observation has a posi-
tive impact on rehabilitation of motor deficits after stroke. Neuro- Published online 3 May 2011 in Wiley Online Library
image 2007;36 Suppl 2:164–173. (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 negative pathology. Only 1 previous report indicates similar-
patient gradually became dysphagic. At further follow-up he pre- ities to our case: a PGRN mutation carrier with an unusual
sented with clear supranuclear ophthalmoplegia, dysphagia, dys- clinical presentation characterized by the co-occurrence of pro-
arthria, dysphonia, and an akinetic-rigid picture with gressive dysarthria, oculomotor abnormalities and buccofacial
camptocormic posture, shuffling gait, and a tendency to fall back- dyskinesias.8 However, the authors excluded PSP on clinical
ward. A diagnosis of possible progressive supranuclear palsy grounds, and neuroimaging showed no significant atrophy.
(PSP) was made according to NINDS-SPSP criteria1 which was Pathological changes were noted in the basal ganglia including
compatible with the brain MR scan (Fig. 1). The sister of the patchy gliosis, but no overt neuronal loss was detected. TDP-
patient was concomitantly diagnosed with PSP at another center. 43-positive inclusions in the striatum and cortex were also
Progranulin (PGRN) and tau mutation tests were performed: reported. Brain stem nuclei examination was negative for both
tau was negative, whereas the PGRN test demonstrated a heter- neuronal loss or gliosis and neurofibrillary tangles or Lewy
ozygous c.813_816delCACT (p.Thr272SerfsX23) mutation bodies. Interestingly, a PSP-like clinical phenotype and a com-
within exon 7 of the gene, a common mutation in northern patible tau neuropathology have been recently described by
Italy.2 Genetic tests performed on the affected sister showed an the same authors in a single patient carrying an LRRK2 muta-
identical positive result.
tion, a gene previously associated with synuclein pathology.9
Progranulin mutations lead to a loss-of-function tau-nega-
Together, this evidence suggests that more genes may be
tive pathology, which is generally clinically expressed within
involved in determining PSP phenotypes. Further genetic testing
the FTLD and CBD spectrum.3 Conversely, PSP has a distinc-
may be necessary in familial PSP cases where tau mutations are
tive neuropathological phenotype that is specifically related to
absent, particularly if atypical clinical features are present.
the group of tauopathies, particularly to the mutation of the
Moreover, the novel association reported here further expands
MAPT gene (FTDP-17). Asymmetric parkinsonism may be
the clinical borders encompassed by PGRN mutations.
associated with PGRN mutations, often developing a picture
of tau-negative CBD, although the term FTDP-17 (PGRN) Lucio Tremolizzo, MD, PhD,1,2* Francesca Bertola, PhD,3
has come into use.4 PGRN mutations are known to lead to Giorgio Casati, PhD,3 Alberto Piperno, MD,3
particular variations in phenotype because they may deter- Carlo Ferrarese, MD, PhD,1,2
mine, for example, Alzheimer’s disease phenotypes, amyotro- and Ildebrando Appollonio, MD1,2
phic lateral sclerosis, or rapidly progressive dementia often
evolving to a secondary diagnosis (mostly CBD) within 2 1
Department of Neurology, S. Gerardo Hospital,
years.5 The single clinical phenotype never described before in Monza, Italy; 2Department of Neuroscience and
association to PGRN is PSP. In fact, PGRN mutations have Biomedical Technologies, University of
not previously been reported in clinically diagnosed PSP,6 and Milano-Bicocca, Monza, Italy; and 3Consortium
PSP is still regarded as a disease with a generally univocal cor- of Human Molecular Genetics, University of
respondence between clinical and pathological diagnosis, that Milano-Bicocca, Monza, Italy
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 References
comprehensive definition of our case might be ‘‘PSP-like,’’ 1. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the
describing a clinical mimic of this tauopathy expressing a tau- diagnosis of progressive supranuclear palsy (Steele-Richardson-

Olszewski syndrome): report of the NINDS-SPSP international Interestingly, we did not find any reports of neuropathy as
workshop. Neurology 1996;47:1–9.
an adverse event in studies involving levodopa (or any other
2. Tremolizzo L, Gelosa G, Galbussera A, et al. Higher than expected antiparkinsonian drug) in either the drug- or placebo-treated
progranulin mutation rate in a case series of Italian FTLD patients.
Alzheimer Dis Assoc Disord 2009;23:301. subjects. We also found that the frequency of adverse events
3. Kertesz A. Clinical features and diagnosis of frontotemporal de- suggestive of neuropathy did not differ significantly between
mentia. Front Neurol Neurosci 2009;24:140–148. the treated and placebo groups in any of the included trials.
4. Boeve BF, Hutton M. Refining frontotemporal dementia with Although only 1 trial provided a direct comparison between
parkinsonism linked to chromosome 17: introducing FTDP-17 levodopa and placebo,6 a total of 12,543 patients in the
(MAPT) and FTDP-17 (PGRN). Arch Neurol 2008;65:
460–464. selected trials were exposed to levodopa while taking other
5. Moreno F, Indakoetxea B, Barandiaran M, et al. ‘‘Frontotemporo-
adjuvant therapeutic compounds.
parietal’’ dementia: clinical phenotype associated with the c.709– In a recent case–control study, Toth et al2 reported a higher
1G>A PGRN mutation. Neurology 2009;73:1367–1374. frequency of polyneuropathy in PD patients (55%) than in
6. Borroni B, Archetti S, Alberici A, et al. Progranulin genetic variations age- and sex-matched subjects from the general population
in frontotemporal lobar degeneration: evidence for low mutation fre-
quency in an Italian clinical series. Neurogenetics 2008;9:197–205.
(9%). The mean age of the PD patients with neuropathy was
72.1 years compared with 63.2 years for those without neu-
7. Donker Kaat L, Boon AJ, Kamphorst W, Ravid R, Duivenvoorden
HJ, van Swieten JC. Frontal presentation in progressive supranu- ropathy. It is known that clinical trials tend to enroll younger
clear palsy. Neurology 2007;69:723–729. and healthier patients, and this might have contributed to the
8. Wider C, Uitti RJ, Wszolek ZK, et al. Progranulin gene mutation absence of neuropathy reports in PD studies.
with an unusual clinical and neuropathologic presentation. Mov Only 7 of the included studies contained follow-up data
Disord 2008;23:1168–1173.
beyond 52 weeks, and it is possible that levodopa can cause
9. Wider C, Dickson DW, Wszolek ZK. Leucine-rich repeat kinase 2
gene-associated disease: redefining genotype-phenotype correlation. neuropathy after more prolonged exposure. An eventual
Neurodegener Dis 2010;7:175–179. 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
Has ‘‘Levodopa-Induced Neuropathy’’ designed for evaluating drug safety and that investigators fre-
Been Reported in Parkinson’s Disease quently overlook mild or unexpected adverse events such as
Clinical Trials? 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,
An association between levodopa and the occurrence of at minimum one should assume that severe manifestations are
peripheral neuropathy in Parkinson’s disease (PD) patients absent. These conclusions cannot be extrapolated for sub-
has been proposed by Toth et al1,2 and is supported by case groups of patients who are usually excluded from clinical tri-
reports of neuropathy in patients treated with Duodopa.3–5 als, for example, patients with severe or prolonged disease,
These reports led to a safety alert concerning the effects of significant comorbidity, or advanced age.
levodopa on the peripheral nervous system. In conclusion, the safety data from PD clinical trials do
To quantify the frequency with which neuropathy is not support an association between antiparkinsonian drugs
reported as an adverse effect in PD trials, we conducted a and the development of neuropathy.
systematic review of randomized parallel-design trials that
compared marketed antiparkinsonian drugs with placebo.
Our search included eligible trials that were published before Tiago Teodoro, MD, Daniela Pires, MD,
December 2009. The primary outcome from our study was Mário M. Rosa, MD, Miguel Coelho, MD,
the frequency with which neuropathy, polyneuropathy, or Cristina Sampaio, MD, PhD, and
mononeuropathy was reported as an adverse event. The sec- Joaquim J. Ferreira, MD, PhD*
ondary outcomes were clinical signs or symptoms possibly
related to neuropathy and reported as an adverse event. Neurological Clinical Research Unit, Instituto de
From a total of 795 identified studies, 79 satisfied the Medicina Molecular, Lisbon School of Medicine,
selection criteria and were included in our analysis. These Lisbon, Portugal
studies involved 10,620 patients treated with antiparkinso-
nian agents and 6710 patients treated with placebo.
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.
------------------------------------------------------------
*Correspondence to: Joaquim J. Ferreira, Neurological Clinical 2. Toth C, Breithaupt K, Suchowersky O, et al. Levodopa, methylma-
Research Unit, Instituto de Medicina Molecular, Lisbon School of lonic acid, and neuropathy in idiopathic Parkinson disease. Ann
Medicine, Lisbon, Portugal; [email protected] Neurol 2010;68:28–36.
3. Manca D, Cossu G, Murgia D, et al. Reversible encephalopathy
Relevant conflicts of interest/financial disclosures: Nothing to report. and axonal neuropathy in Parkinson’s disease during duodopa
Full financial disclosures and author roles may be found in the online therapy. Mov Disord 2009;24:2293–2294.
4. Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion
Published online 12 May 2011 in Wiley Online Library for advanced Parkinson’s disease: 12-month treatment outcome.
(wileyonlinelibrary.com). DOI: 10.1002/mds.23760 Mov Disord 2007;22:1145–1149.

5. Urban P, Wellach I, Weis J, et al. Subacute axonal neuropathy in age and disease duration (0.29, P ¼ .025; and 0.29, P ¼
Parkinson’s Disease with cobalamine and vitamin B6 deficiency
under duodopa therapy. Mov Disord 2010;25:1748–1752.
.028, respectively) and to be moderately correlated with
UPDRS III score (0.44, P < .001).
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. 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
Relationship Between Sleep and that showed the highest correlation with the PDSS total
score were the gastrointestinal and urinary domains (Table
Dysautonomic Symptoms Assessed 1). On the other hand, when grouping the PDSS items,5
by Self-Report Scales ‘‘nocturnal motor symptoms’’ (items 10–13) and ‘‘nocturia’’
(items 8 and 9) both showed a moderate correlation with
total SCOPA-AUT score (Table 1).
Sleep disturbances and autonomic dysfunction have
After introducing the variables into a stepwise linear
been implicated in Parkinson’s disease (PD) since the first
regression model using PDSS as the dependent variable, we
descriptions of this condition.1 A possible relationship
found that SCOPA-AUT alone accounted for 27.3% of the
between dysautonomia and sleep disorders is suggested by
the anatomical proximity of their regulatory centers in the variance in the PDSS (F ¼ 21046; P < .001).
brain stem.2
The objective of this study was to explore the clinical Discussion
relationship between self-reported autonomic and sleep
dysfunction. 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
Patients and Methods also showed a similar relationship.6 Four domains were
This was a cross-sectional study including a total of 60 found to be significantly correlated with the PDSS total
patients, all diagnosed with PD3 and recruited consecutively score: the gastrointestinal, urinary, pupilomotor, and ther-
on attendance at a movement disorders clinic. Informed con- moregulatory domains. The result for the urinary domain
sent was required before enrollment. All patients underwent comes as no surprise, as nocturnal urinary symptoms directly
a complete neurological examination including completion influence the quality of sleep.
of the Unified Parkinson Disease Rating Scale (UPDRS). Au- This is the first study exploring the relationship between
tonomic dysfunction was assessed with the SCOPA-AUT sleep and autonomic nervous system disorders using self-
scale,4 and sleep dysfunction was assessed using the Parkin- reported scales. It illustrates high rates of autonomic symp-
son’s Disease Sleep Scale (PDSS) and Epworth Daytime toms and sleep disturbance in PD and confirms a strong cor-
Sleepiness Scale (Epworth). 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
Statistical Analysis correlation. However, this may well be a simplification of a
Means and standard deviations were determined for the much more complex relationship, and further research is
quantitative variables. Stepwise regression analyses were per- required.
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. Beatriz Tijero, MD,1 Johanne Somme, MD,1
Juan Carlos Gómez-Esteban, MD, PhD,1*
Koldo Berganzo, MD,1 Ishan Adhikari, MD,2
Results Elena Lezcano, MD, PhD,1 Iker Bilbao, MD,1
The mean SCOPA-AUT total score was 20.9 6 12.1, and Iñigo Garamendi, MD,1 and Juan José Zarranz, MD, PhD1
urinary was the most affected domain (28.4 6 21.6). The 1
mean PDSS total score was 113 6 16.3. The total score on Movement Disorders Unit, Neurology
the SCOPA-AUT was found to be weakly correlated with Department, Hospital de Cruces, Baracaldo,
Vizcaya, Spain; and 2Dysautonomia Center,
Langone Medical Center, New York University,
New York, New York, USA
------------------------------------------------------------
*Correspondence to: Juan Carlos Gómez-Esteban, Movement
Disorders Unit, Neurology Department, Hospital de Cruces,
Baracaldo, Vizcaya, Spain; [email protected]
References
Relevant conflicts of interest/financial disclosures: Nothing to report. 1. Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychia-
Full financial disclosures and author roles may be found in the online try Clin Neurosci. 2002;14:223–236; discussion 222.
2. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN,
Published online 12 May 2011 in Wiley Online Library Braak E. Staging of brain pathology related to sporadic Parkinson’s
(wileyonlinelibrary.com). DOI: 10.1002/mds.23761 disease. Neurobiol Aging. 2003;24:197–211.

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- 5. Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson’s disease sleep
nosis of Lewy body Parkinson’s disease. Neurology. 2001;57: scale: a new instrument for assessing sleep and nocturnal disability in
1497–1499. Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2002;73:629–635.
4. Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment 6. Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout
of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. AM, van Hilten JJ. Patient-reported autonomic symptoms in Par-
Mov Disord. 2004;19:1306–1312. kinson disease. Neurology. 2007;69:333–341.

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LETTERS: NEW O B S E RVAT I O N S

Movement Disorders, Vol. 26, No. 10, 2011 1951

Jan Rusz, MSc,1,2,3 Roman Čmejla, MSc, PhD,1

1952 Movement Disorders, Vol. 26, No. 10, 2011

Movement Disorders, Vol. 26, No. 10, 2011 1953

1954 Movement Disorders, Vol. 26, No. 10, 2011

René Reese, MD,1 Jan Herzog, MD, PhD,1

Departments of 1Neurology, 2Neurosurgery, and

Movement Disorders, Vol. 26, No. 10, 2011 1955

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

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

Movement Disorders, Vol. 26, No. 10, 2011 1957

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

supports the observation that the distinct components of

Movement Disorders, Vol. 26, No. 10, 2011 1959

1960 Movement Disorders, Vol. 26, No. 10, 2011

Movement Disorders, Vol. 26, No. 10, 2011 1961

1962 Movement Disorders, Vol. 26, No. 10, 2011

4. Bloomer JC, Clarke SE, Chenery RJ. In vitro identiﬁcation of the

Action Observation Treatment

Movement Disorders, Vol. 26, No. 10, 2011 1963

1964 Movement Disorders, Vol. 26, No. 10, 2011

Movement Disorders, Vol. 26, No. 10, 2011 1965

1966 Movement Disorders, Vol. 26, No. 10, 2011

Movement Disorders, Vol. 26, No. 10, 2011 1967

SCOPA AUT Gastrointestinal Urinary Cardiovascular Thermoregulatory Pupil Sexual

1968 Movement Disorders, Vol. 26, No. 10, 2011

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