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Parkinsonism and Related Disorders xxx (2015) 1e6

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Parkinsonism and Related Disorders

journal homepage: www.elsevier .com/locate/parkreldis

Long-term course of orthostatic tremor in serial posturographicmeasurement

K. Feil a, b, *, N. B€ottcher a, b, F. Guri a, S. Krafczyk a, b, F. Sch€oberl a, b, A. Zwergal a, b,M. Strupp a, b

a Department of Neurology, University Hospital Munich, Campus Grosshadern, Munich, Germanyb German Center for Vertigo and Balance Disorders, University Hospital Munich, Campus Grosshadern, Munich, Germany

a r t i c l e i n f o

Article history:Received 30 November 2014Received in revised form26 May 2015Accepted 27 May 2015

Keywords:Clinical neurologyOrthostatic tremorLong-term courseEMG

* Corresponding author. German Center for Vertigoversity Hospital Munich Campus Grosshadern MMunich, Germany.

E-mail addresses: katharina.feil@med.uni-muenboettcher@med.uni-muenchen.de (N. B€ottcher), Flade (F. Guri), Siegbert.krafczyk@med.uni-muenchenschoeberl@med.uni-muenchen.de (F. Sch€oberl),muenchen.de (A. Zwergal), Michael.strupp@med.uni-

http://dx.doi.org/10.1016/j.parkreldis.2015.05.0211353-8020/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: K. Feil, et aRelated Disorders (2015), http://dx.doi.org/1

a b s t r a c t

Objective: Primary orthostatic tremor (OT) is a rare neurological disease of unknown pathophysiologycharacterized by a high-frequency tremor mainly of the legs when standing. The aim of this study was toexamine its long-term course by subjective estimation and objective recording by serial posturographyand to obtain further standardized epidemiological and clinical data on patients with OT.Methods: A clinical cohort of 37patients with the diagnosis of primary OT was screened for this longi-tudinal follow-up study. Eighteen patients consented to participate. During study visit all patients un-derwent a standardized neurological examination and completed subjective scales and scores.Posturographic recordings at follow-up were compared to prior clinical posturographic measurements in15cases.Results: In our cohort the mean duration of symptoms was 14.1 ± 6.8 years. Subjectively, 78% of patientsreported progression of the disease. Posturographic data (5.4 ± 4.0 years) revealed a significant increaseof the total sway path (standing on firm ground with eyes open) from 2.4 ± 1.3 to 3.4 ± 1.4 m/min(p ¼ 0.022) and of the total root mean square values from 9.8 ± 4.3 to 12.4 ± 4.8 mm (p ¼ 0.028). None ofthese observations are explained by aging of the patients. Mean frequency of the tremor did not changeover time (14.7 ± 1.9 Hz vs. 14.9 ± 2.0 Hz at follow-up). Clinically, most patients had signs of cerebellardysfunction and a substantial portion also showed proprioceptive deficits in the long-term course.Conclusions: This long-term follow-up study indicates, that primary OT is a progressive disorder.Furthermore, the clinical observation of cerebellar dysfunction in most OT patients in the long-termcourse might indicate an important role of the cerebellum in its pathophysiology.

© 2015 Elsevier Ltd. All rights reserved.

1. Introduction

Orthostatic tremor (OT) is a rare disorder with unknown prev-alence first described in 1984 [1,2]. The disease is associated with apathognomonic 13e20 Hz pattern of synchronized bursting ofmuscle activity during postural activity with patients clinicallycomplaining of dizziness, restlessness, unsteadiness or discomfort

and Balance Disorders Uni-archioninistrasse, 15, 81377

chen.de (K. Feil), Nicolina.via.guri@med.uni-muenchen..de (S. Krafczyk), Florian.Andreas.zwergal@med.uni-

muenchen.de (M. Strupp).

l., Long-term course of orthos0.1016/j.parkreldis.2015.05.0

while standing [2,3]. The diagnosis can be confirmed by surfaceelectromyography (EMG) recordings (e.g. from the quadricepsmuscle).

Orthostatic tremor can be symptomatic or primary. Formerneurophysiological and PET studies suggest a spontaneous centraloscillator located in the pons or cerebellum [4,5]. This view hasfurther been supported by symptomatic cases of OT after pontinebrainstem lesions [4,6] and in patients with idiopathic cerebellaratrophy [7,8]. An overlap of primary OT with Parkinson's disease,vascular parkinsonism, primary gait initiation failure, progressivesupranuclear palsy (PSP) and restless legs syndrome was described[9,10].

There are several treatment approaches to OT [9,11,12]. Themostcommonly used medication for OT is clonazepam, but treatmentresponse is only modest to poor and inconsistent.

Epidemiological data on the natural course of primary OT is

tatic tremor in serial posturographic measurement, Parkinsonism and21

K. Feil et al. / Parkinsonism and Related Disorders xxx (2015) 1e62

largely lacking, especially since the diagnosis is rarely made. Mostpublications refer to case reports [13,14]. In a case series of 41 pa-tients, the course of the disease was investigated by means of thesubjective impressions of the physicians [9]. In the largest caseseries of 45 patients published in 2014, 11/30 cases of OT describeda subjective worsening over the mean follow-up period of 54.4months [10]. To the best of our knowledge, there are no data onobjective measurements in OT patients over time. Therefore, themajor aim of this study was to evaluate the course of the disease inan objective way using serial posturographic recordings.

2. Methods

2.1. Patients

The medical records of all patients diagnosed with OT in theDepartment of Neurology and the German Center for Vertigo andBalance Disorders at the University of Munich between 1993 and2013were reviewed. All in all, we had a clinical cohort of 37 patients:all these patients fulfilled the diagnostic criteria for OT [3]. Symp-tomatic cases were excluded. Out of this clinical cohort, 18 patientswere included in the study and seen in a follow-up visit (for furtherdetails see Supplemental Fig. 1) Information about demographic,epidemiological and clinical features, including a detailed stan-dardized medical and drug history, was collected during the follow-up study visit, entered into a database and analysed.

2.2. Neurological examination

The patients received a standardized neurological, neuro-ophthalmological and neuro-otological examination. This includedthe head-thrust test, evaluation for spontaneous nystagmus withFrenzel's goggles in primary position and during gaze deviations,gaze-evoked nystagmus, smooth pursuit, saccades, optokineticnystagmus, visual fixation suppression of the VOR, reboundnystagmus, head-shaking nystagmus and determination of thesubjective visual vertical (SVV). The eye position in roll-plane wasmeasured with a scanning laser ophthalmoscope in all patients.

2.3. Posturography

Posturographic measurements were carried out in the uprightposition using the standard protocol with ten different conditionswith increasing difficulty (for ref. see Ref. [15]). As more than 50% ofour patients were too instable to perform the full examination andneeded help because of a high risk of falls in conditions 2e10, onlytest condition 1 (standing on firm ground with eyes open) wasanalysed. The total body sway of 30 seconds of the posturographicmeasurement provided the sway path values [m/min]. Further-more, root mean square (RMS) [mm] and frequency spectrum be-tween 11e19 Hz (FFT) of the z axis [kgf/Hz] of the measurementswere obtained (as an example see Fig. 1A and B).

2.4. Subjective scales and scores

In addition, different scores to assess falls and balance in pa-tients with OTwere provided. All patients completed the Activities-specific Balance Confidence (ABC) scale and the Falls Efficacy Scale-International (FES-I). Quality of life was evaluated using the Euro-Qol-5D-5L questionnaire (EQ-5D-5L).

2.5. Standard protocol approvals, registrations, and patient consent

Ethics committee board approval was obtained for the study.Written informed consent was obtained from all participants. All

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clinical investigations were conducted according to the principlesof the Declaration of Helsinki.

2.6. Statistical analysis

Posturography data were collected and evaluated in MATLAB(MathWorks. Inc., Natcik, MA), other data were evaluated usingExcel (Microsoft, Redmond, WA) spreadsheet software. Statisticalanalysis was performed using SPSS (IBM, Armonk, NY).Figures were designed with GraphPad Prism (v5, GraphPad Soft-ware Inc., La Jolla, CA, USA). As data were not normally distributed,nonparametric paired testing was performed using the Wilcoxonsigned-rank test and nonparametric unpaired testing was doneusing the ManneWhitney test. To express the correlation we usednonparametric testing with Spearman R. Differences were consid-ered significant if p < 0.05.

3. Results

3.1. Patient characteristics

Eighteen patients were included in the study (for further detailson clinical data see Table 1 for group-level data and Supplementalmaterial Table 1 for individual patients' clinical data).

3.2. Neurological and neuro-ophthalmological examination

All patients had pathological neuro-ophthalmological findingsand showed central ocular motor dysfunctions, at least saccadicsmooth pursuit e but most of the patients had further findings (seeTable 2) with gaze-evoked nystagmus, head-shaking nystagmusand a pathological head-thrust test. One patient (patient no. 7) hadan essential tremor. In terms of clinical characteristics, 16 out of our18 patients showed impaired reflexes of the legs and pallhypaes-thesia. All patients showed postural instability in the push-and-pulltest. Romberg's test was positive in all but two patients (patientsno. 8 and no. 10). We found further cerebellar signs in 14 patients,with most of the patients showing dysmetria in the finger-chase/nose-finger test, intention tremor and irregular fast alternatinghand movements (for further details see Table 2).

3.3. Subjective scales and scores

Results on subjective individual scales and scores are presentedin Table 3.

3.4. Subjective and objective course of disease

All of the patients with primary OT subjectively observed aslowly progressive onset of the symptoms. In the follow-up ex-amination, all patients were asked whether they believed that theirdisease had remained stable, worsened or improved over the yearsas a categorical interpretation. Thirteen patients reported a gradualincrease of complaints over the years, one a stable status (patientno. 17), and four an improvement of the symptoms. The objectivecourse of the disease was examined using serial posturographicmeasurements with patients standing on firm ground and witheyes open. Mean duration of follow-up between recordings was5.4 ± 4.0 years (range 1e135 months). There was a significantworsening in total sway path and total root mean square valuesover time. At the first examination the mean total sway path was2.4 ± 1.3 and it increased to 3.4 ± 1.4 m/min (p ¼ 0.022, n ¼ 15) atfollow-up (see Fig. 1C, F). Total root mean square values (RMS)increased from 9.8 ± 4.3 to 12.4 ± 4.8 mm at follow-up (p ¼ 0.028,n ¼ 15) (see Fig. 1D). The spectrum of frequency from 11e19 Hz on

tatic tremor in serial posturographic measurement, Parkinsonism and21

Fig. 1. A and B: Body sway path and frequency plot of one patient (patient no. 14) standing on firm ground with eyes open showing two frequency peaks at 5.0 Hz and (typicalorthostatic tremor frequency peak) at 13.5 Hz (CeF): Changes of posturographic measurements in follow-up showed by total sway path (SP) values [m/min] (C), total root meansquare values (RMS) [mm] (D) and integral of the frequency spectrum on the z axis (FFT Z) 11e19 Hz [N/Hz] (E) of patients with primary orthostatic tremor (OT) standing on firmground with eyes open, changes of SP in percent starting at normalized first value at 100% (F).

K. Feil et al. / Parkinsonism and Related Disorders xxx (2015) 1e6 3

the z-axis changed from 43.2 ± 25.4 to 80.6 ± 43.9 N/Hz (p ¼ 0.007,n ¼ 15) at follow-up (see Fig. 1E).

Patients on medication did not differ in terms of total sway pathcompared to patients without medication (on medication: meantotal sway ratio 0.93 ± 0.43, without medication 0.67 ± 0.41,p ¼ 0.18). There was a strong correlation between the individualchange of total sway path and the time to follow-up (Spearman r0.52, p ¼ 0.04).

Mean frequency of OT was 14.7 ± 1.9 in the first examinationand 14.9 ± 2.0 Hz in follow-up examination (p ¼ 0.095). The in-dividual frequency of tremor of the patients with OT did notchange significantly at follow-up (p ¼ 0.09). Three patients hadtwo frequency peaks in follow-up (patients no. 3, 17 and 19). Onepatient had three frequency peaks (patient no. 7) (for details seeTable 2).

A change in total sway path of >20% was quantified as a

Please cite this article in press as: K. Feil, et al., Long-term course of orthosRelated Disorders (2015), http://dx.doi.org/10.1016/j.parkreldis.2015.05.0

categorical objective progression/regression. This was correlatedwith the absolute value of the subjective categorical evaluation ofthe course of disease by the patients. Here we found a mediumcorrelation between the subjective and the objective course of thedisease (Spearman R 0.45, p ¼ 0.045), that means that 73% of thepatients were able to estimate their disease progression properly.Worsening of balance control over time was also confirmed byserial artificial network analysis of posturographic data.

4. Discussion

The aim of our study was to investigate the long-term courseof primary OT by subjective estimation and objective recordingby means of posturography. The three major findings are asfollows:

First, 78% of our patients claimed a subjective worsening of the

tatic tremor in serial posturographic measurement, Parkinsonism and21

Table 1Group-level clinical data of patients with primary orthostatic tremor collected at follow-up study visit.

Sex Age Duration ofdisease (years)

Subjective course ofdisease

Family history ofneurological disease

Alcoholabuse inhistory

Sensitivity toalcoholconsumption

Subjective course ofthe symptoms overthe day

Currentmedicationfor OT

Subjectiveefficacy

8 male/10female

Mean age:70.5 ± 5.7 years(range 54e78)Female: mean age68.2 ± 6.9Male: mean age74.4 ± 2.3

Mean 14.1 ± 6.8years (range 1e26).

3 patients:improvement(patient no. 1, 2, 16)1 patient: stable(patient no. 17)14 patients:worsening

6 patients: positiveED: patient no. 1,dementia: patientno. 2, 18Neuropathy: patientno. 12OT: patient no. 6, 11a

(mother)12 patients:unremarkable

12patients:no6 patients:yes

5 patients: notreported6 patients: none3 patients:subjectiveimprovement4 patients:subjectiveworsening

2 patients: increase8 patients: decrease8 patients: constant

10 patientsonmedication8 patients:nomedication

4 Yes6 no

Groups' characteristics, presented as group-level data and categorized by gender, age, duration of disease (since the beginning of symptoms), anamnestic features andmedication for orthostatic tremor. Abbreviations: OT ¼ orthostatic tremor, ED ¼ encephalomyelitis disseminata, f ¼ female, m ¼ male. For individual data see Supplementalmaterial Table 1.

a Patients no. 6 and 11: siblings.

K. Feil et al. / Parkinsonism and Related Disorders xxx (2015) 1e64

symptoms. This subjective progression was also described in othercase series in 2001 with 6/28 patients reporting a worsening ofsymptoms; in four out of these six patients, a spread of the tremor

Table 2Clinical data of patients containing frequency of OT at first clinical visit and characteristi

Patient Sex Age Frequency oftremor (Hz) atfirstexamination

Frequency oftremor (Hz) atfollow-up

Durationof disease(years)

Duration offollow-up(months)

Neuro-ophthalmologfindings

1 f 54 17.2 17.0 7 17 1, SVV deviat2 f 73 16.3 16.5 26 15 1, 2, 6, ocular3 m 77 16.8 5.3/17.5 23 137 1, 2, 3 (left), 7

horizontal pealternating ny

4 m 72 14.0 13.5 23 31 1, 5 (bilateral5 f 62 16.0 16.0 15 63 1, 3 (downbe

deviation6a m 72 14.5 16 / 1, 2, 3 (down

(bilateral)7 f 72 5.5/11.5/16.5 5.5/11.0/17.0 8 37 1, 2, 3 (left), 5

(bilateral)8 f 63 13.5 14.0 15 86 1, 2, 3 (left);

deviation9 f 69 5.5./15.5 5.5/15.0 19 134 1, 2, 6

10 m 72 16.7 17.0 10 137 111a f 78 14.0 18 / 1, 2, 5 (bilate

hypometric s12 f 72 15.5 16.0 20 135 1

13 m 77 14.0 14.5 18 105 1, 2, 5 (bilatertorsion unilat

14 m 73 11.0 11.5 8 36 1

15 m 71 13.5 13.0 1 1 1, 2, 3 (left), 5(bilateral), 6,hypometric sSVV deviation

16 f 72 10.5 11.0 5 3 1, 6 (vertical)hypometric s

17 m 73 7.2/14.2 7.3/14.0 11 51 1, 2, 5 (unilat18 f 67 15.5 9 / 1, 2, 3 (left), 5

(bilateral)

Clinical characteristics of the patients with primary orthostatic tremor, categorized byAbbreviations: f ¼ female, m ¼ male.Neuro-ophthalmological findings: 1 ¼ saccadic smooth pursuit; 2 ¼ gaze-evoked nystagmthrust test (uni- or bilateral); 6 ¼ impaired visual fixation suppression of the VOR; 7 ¼ pNeurological findings: 1¼ dysmetria in nose-finger-test, 2¼ tremor in finger chase, 3¼ abtremor, 6 ¼ postural tremor, 7 ¼ rigidity, 8 ¼ dysarthria.

a Patients no. 6 and 11: siblings.

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to other parts of the body was documented [9]. In the largest caseseries from 2014, 11/30 patients reported progression of diseaseover an average follow-up time of 54.5 months [10]. However, this

cs of OT at study visit as well as clinical data collected at study follow-up visit.

icalNeurological findings Impaired ankle reflexes

and pallhypaesthesiaor pallanaesthesia

Posturalinstability

Romberg

ion 3 no yes positivetorsion yes yes positive,riodicstagmus

1, 2, 3 yes yes positive

) 3, 6 yes yes positiveat), SVV 1, 2, 3 yes yes positive

beat), 5 1, 2, 3 yes yes positive

1, 2, 3, 4, 5, 6 yes yes positive

SVV 1, 2, 6 yes yes negative

1, 2, 3, 4, 5, 6, headtremor

yes yes positive

1, 2, 6 yes no negativeral),accades

1, 2, 3, 4 yes yes positive

1, 2, pronation forearmholding test

yes yes positive

al), ocularerally

1, 2, 5 yes yes positive

2, 3, 5, muscle atrophy oflower limb (right > left)(right > left)

yes yes positive

accades,

1, 2, 3, 8 yes yes positive

,accades

bradydysdiadochokineseof tongue, 8, pronationforearm holding test

no yes positive

eral right) 2, 3, 6, 7 yes yes positive2, 5, 6, drooping mouthon right side

yes yes positive

patient number, neuro-ophthalmological and neurological findings and symptoms.

us; 3 ¼ head-shaking nystagmus; 4 ¼ rebound nystagmus; 5 ¼ pathological head-athological optokinetic reflex; SVV: subjective visual vertical.normal heel-shin slide, 4¼ irregular fast alternating handmovements, 5¼ intention

tatic tremor in serial posturographic measurement, Parkinsonism and21

Table 3Subjective scales and scores of patients at follow-up.

FES-I-score ABC-score EQ-5D-5L EQ-5D-5L VAS

All 35.6 ± 10.3 46.7% ± 22.4 0.74 ± 0.21 62.2% ± 26.0Women 31.9 ± 9.7 (n ¼ 10) 43.2% ± 22.5 0.68 ± 0.23 58.3% ± 26.4Men 38.5 ± 0.9 (n ¼ 8; p¼ 0.83) 51.1% ± 24.4 (p¼ 0.51) 0.84 ± 0.17 (n ¼ 7; p¼ 0.12) 67.9% ± 28.7 (n ¼ 7; p¼ 0.62)Duration< 10 years 33.8 ± 12.5 (n ¼ 6) 44.7% ± 27.6 0.73 ± 0.30 68.0% ± 32.3Duration� 10 years: 36.4 ± 10.0 (n ¼ 12) (p¼ 0.78) 47.7% ± 21.6 (p¼ 0.97) 0.75 ± 0.17 (n ¼ 11; p¼ 0.88) 59.1% ± 24.7 (n ¼ 11; p ¼ 0.54)

Subjective scales and scores of patients with primary OT at follow-up visit.Falls Efficacy Scale-International (FES-I) (total score range from 16 (no concern about falling) to 64 (severe concern about falling)).Activities-specific Balance Confidence (ABC) scale (ABC-score) (>80% high level of physical functioning, 50e80%moderate level of physical function, <50% low level of physicalfunction).Quality of life of the patients with OT was evaluated using the Euro-Qol-5D-3L questionnaire (EQ-5D-5L). EQ-5D-5L (total score range from 0 to 1) and visual analogue scale(VAS) (range VAS from 0 to 100).

K. Feil et al. / Parkinsonism and Related Disorders xxx (2015) 1e6 5

progression of symptoms was described by clinical impression andinformation from the patients.

Second, the posturographic measurements revealed a meanincrease of total sway path of 45% and of total RMS of 27% overtime. These findings cannot be explained by simple aging of thepatients as long-term follow-up studies with posturographyproved posturographic measurements to remain stable over timeand not to correlate with age [16]. Instead, our posturographicdata indicate that OT is a progressive disease which is in line withthe subjective estimations of OT patients as was shown in this andpast studies as well [9,10]. Hence, there is an analogy with thecourse of essential tremor (ET) [17]. Further on, we found a cor-relation between the time to follow-up and the change of totalsway path in our OT patients: the longer the follow-up was be-tween the examinations, the more our patients were affected interms of total sway path.

Third, all the patients had additional abnormal findings in theneurological examination: at least mild cerebellar ocular motordysfunction such as saccadic smooth pursuit was found in each ofour patients with most of them also showing different forms ofnystagmus and with 14 out of 18 showing additional ataxia of atleast one limb. 16 out of 18 patients had pallhypaesthesia anddecreased reflexes in the lower limbs. However none of our pa-tients had signs of parkinsonism. This is in contrast to two paststudies on OT with 41 respectively 45 patients, since the mainabnormal neurological findings in addition to OT there were signsof parkinsonism and restless legs syndrome (RLS) [9,10] At least 1 ofthe 45 patients exhibited cerebellar ataxia and in a small case seriesof 3 patients an association of OT with cerebellar dysfunction wasshown [7,10]. In this context it has to be outlined that we did veryaccurate and standardized neuro-opthalmological and neuro-otological examinations which allowed us also to detect discretesubclinical ocular motor abnormalities. So it might be possible thatthis slight abnormalities haven been overlooked in past studies onOT patients. Furthermore, all the existing cases of OT patients in theliterature support the idea that the clinical phenotype is quitevariable. Unfortunately, we cannot make clear statements whetherthese cerebellar and also proprioceptive deficits were progressiveover time, since the very detailed neuro-ophtalmological andclinical examinations in our patients could not be evaluatedretrospectively.

Considering the clinical findings in our patients the progressionof unsteadiness over time can be either due to cerebellar dysfunctionor marked proprioceptive deficits. In a former study a dissociationbetween subjective and objective unsteadiness in OT patients wasfound [18]. The authors suggested that this observation is probablydue to proprioceptive afferent deficits, since visual and propriocep-tive sensory feedback are the predominant mechanisms to maintainstability during quiet standing. Impaired proprioception decreasesthe detection of the small movements that are important to makepostural adjustments. However, increased unsteadiness did not

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result in an increase of the total sway path in OT patients in thisstudy aswe objectivelymeasured by serial posturography. Regardingthis finding and also the fact that some of our patients showed asecond frequency peak in the spectrum of 3e5 Hz, as was shown tobe a correlate of impaired function of the vermis [19], we wouldsuggest that cerebellar dysfunction plays an important role for theincreased unsteadiness in our patients [4,20,21]. The observation in 8out of 18 OT patients with unsteadiness being worse in the morningand describing an improvement during daytime shares high simi-larities with downbeat nystagmus (DBN), a cerebellar disorder [22].On the other hand, in another tremor disorder, namely ET, post-mortem studies identified structural cerebellar changes [23e25]indicating that Purkinje cell degeneration may be part of the path-ogenesis of ET and assuming that ET could be of neurodegenerativecause [26,27]. However, this results are controversial and need tofurther be examined.

This study indicated that the effectiveness of the medicationsused in OT is poor, as already described elsewhere [9]. The group ofpatients on medication did not show any significant changes in thetotal sway path ratio in posturography. This further shows thelimited effectiveness of the available medications.

This study has some limitations. First of all, the study did not runprospectively. So, the time to follow-up for each patient differedfrom several months to several years. Second, the number of pa-tients (15) with complete posturographic follow-up examinationwas rather small. On the other hand, the disease is very rare. Third,more than 50% of patients were on medication at the time of thefollow-up examination. Nevertheless we showed that the medi-cation had no effects on sway path. Of course, another importantpoint is that a potential selection bias cannot be ruled outcompletely. Only 18 out of 32 possible patients from the clinicalcohort participated in our study. However, only 2 patients out of the14 who didn't want to take part claimed that this was because oforthostatic tremor itself (one claiming to have no symptoms at alland one claiming to have too many symptoms). Still, a selectioncannot be ruled out completely.

In conclusion, this was the first study to show an objectiveprogression of symptoms in patients with primary OT over time.Furthermore, there was an association between OT and cerebellardysfunction. These observations support past data form one PET-imaging and lesion studies that brought up the hypothesis ofcerebellar involvement in the pathophysiology of OT [7,8,20]. So itseems worth to further evaluate the role of the cerebellum in OT byfunctional imaging such as fMRI and PET. And if such studies sug-gest a crucial role of the cerebellum in the pathophysiology of OTsymptomatic treatment with drugs formally used for cerebellardisorders would be worth a trial.

Documentation of author roles

Feil: Research project: conception, organisation, execution,

tatic tremor in serial posturographic measurement, Parkinsonism and21

K. Feil et al. / Parkinsonism and Related Disorders xxx (2015) 1e66

statistical analysis (design, execution), manuscript preparation(writing of the first draft, review).

Boettcher: Research project (execution), manuscript prepara-tion (review and critique).

Guri: Research project (execution), manuscript preparation(review).

Krafczyk: Research project (conception, execution), statisticalanalysis (design, review and critique), manuscript (review andcritique).

Schoeberl: Manuscript preparation (review and critique),including medical writing for content.

Zwergal: Research project (conception), statistical analysis (re-view and critique), manuscript preparation (review and critique),including medical writing for content.

Strupp: Research project: conception, statistical analysis (reviewand critique), manuscript preparation (review and critique),including medical writing for content.

Conflict of interest

We certify that there is no conflict of interest with any financialorganization regarding the material discussed in the manuscript.

Funding sources of study

Supported by the German Ministry of Education and Research(BMBF), grant 01EO0901 to the German Center for Vertigo andBalance Disorders (DSGZ).

Financial disclosure

Dr. Feil reports no disclosures. Mrs. B€ottcher reports no disclo-sures. Mrs. Guri reports no disclosures. Dr. Krafczyk reports nodisclosures. Dr. Sch€oberl reports no disclosures. Dr. Zwergal reportsno disclosures. Dr. Strupp is Joint Chief Editor of the Journal ofNeurology, Editor in Chief of Frontiers of Neuro-otology and SectionEditor of F1000. He has received speaker's honoraria from Abbott,UCB, GSK, TEVA, Biogen Idec, Pierre-Fabre and Hennig Pharma.

Acknowledgment

The authors thank Katie Ogston for copyediting this manuscript.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.parkreldis.2015.05.021.

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