ARTICLE OPEN ACCESS

Quality of life predicts outcome of deep brainstimulation in early Parkinson diseaseWM Michael Schuepbach MD Lisa Tonder MS Alfons Schnitzler MD PhD Paul Krack MD PhD Joern Rau

Andreas Hartmann MD PhD Thomas D Halbig MD Fanny Pineau PhD Andrea Falk MD Laura Paschen MD

Stephen Paschen MD Jens Volkmann MD PhD Haidar S Dafsari MD Michael T Barbe MD PhD

Gereon R Fink MD PhD Andrea Kuhn MD Andreas Kupsch MD PhD Gerd-H Schneider MD PhD

Eric Seigneuret MD Valerie Fraix MD Andrea Kistner MSc P Patrick Chaynes MD PhD

Fabienne Ory-Magne MD Christine Brefel-Courbon MD PhD Jan Vesper MD PhD Lars Wojtecki MD PhD

Stephane Derrey MD David Maltete MD PhD Philippe Damier MD PhD Pascal Derkinderen MD PhD

Friederike Sixel-Doring MD Claudia Trenkwalder MD PhD Alireza Gharabaghi MD PhD Tobias Wachter MD

Daniel Weiss MD PhD Marcus O Pinsker MD PhD Jean-Marie Regis MD PhD Tatiana Witjas MD PhD

Stephane Thobois MD PhD Patrick Mertens MD PhD Karina Knudsen MD Carmen Schade-Brittinger

Jean-Luc Houeto MD PhD Yves Agid MD PhD Marie Vidailhet MD PhD Lars Timmermann MD PhD

and Gunther Deuschl MD PhD for the EARLYSTIM study group

Neurologyreg 201992e1109-e1120 doi101212WNL0000000000007037

Correspondence

Dr Deuschl

gdeuschl

neurologieuni-kielde

AbstractObjectiveTo investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation(DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications

MethodsWe performed a secondary analysis of data from the previously published EARLYSTIM study a prospectiverandomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-upwith disease-specific QOL (39-item Parkinsonrsquos Disease Questionnaire summary index [PDQ-39-SI]) as theprimary endpoint Linear regression analyses of the baseline characteristics age disease duration duration ofmotor complications and disease severity measured at baseline with the Unified Parkinsonrsquos Disease RatingScale (UPDRS) (UPDRS-III ldquooffrdquo and ldquoonrdquomedications UPDRS-IV)were conducted to determine predictorsof change in PDQ-39-SI

ResultsPDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups(p lt 005) The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 monthsNo correlation was found for any of the other baseline characteristics analyzed in either treatment group

ConclusionImpaired QOL as subjectively evaluated by the patient is the most important predictor of benefit inpatients with PD and early motor complications fulfilling objective gold standard inclusion criteria forSTN-DBS Our results prompt systematically including evaluation of disease-specific QOL whenselecting patients with PD for STN-DBS

Clinicaltrialsgov identifierNCT00354133

RELATED ARTICLE

EditorialIs outcome of subthalamicnucleus deep brainstimulation in Parkinsondisease predictable

Page 453

From theDepartementdeNeurologie (WMMSAHTDHFPYAMV)HopitalPitie-SalpetriereCentredrsquoInvestigationClinique1422 InstitutduCerveauetdelaMoelleEpiniere InstitutNationaldeSante etenRecherche Medicale Assistance Publique Hopitaux de Paris France Institute of Neurology (WMMS) Konolfingen Department of Neurology (WMMS) University Hospital Bern and University of BernSwitzerlandMedtronic (LT) Minneapolis MN Institute of Clinical NeuroscienceampMedical Psychology andDepartment ofNeurology (AD LW) Medical Faculty Heinrich-Heine-University Dusseldorf GermanyMovement Disorder Unit Neurology (PK) CHU Grenoble Alpes Grenoble Institut des Neurosciences (PK VF A Kistner) University Grenoble Alpes Inserm U1216 (PK VF A Kistner) Grenoble FranceDepartment of Clinical Neurosciences (Neurology) (PK) Faculty of Medicine University of Geneva Switzerland Coordinating Center for clinical trials of the Philipps University of Marburg (JR CS-B) Neuro-chirurgische Klinik im Neurozentrum (AF LP SP J Volkmann KK GD)Christian-Albrechts-Universitat Kiel Neurologische Klinik und Poliklinik (J Volkmann) Universitatsklinikum Wurzburg Department ofNeurology (HSD MTB GRF LT) University Hospital Cologne Research Centre Julich (GRF) Klinik fur Neurologie (TDH A Kuhn A Kupsch) and Klinik fur Neurochirurgie (G-HS) Campus VirchowCharitendashUniversitatsmedizin Berlin Praxis Kupsch (A Kupsch) Berlin Germany Service de Neurochirurgie (ES) and Service de Neurologie (VF) Hopital Michallon Centre Hospitalo-Universitaire GrenobleDepartmentsofNeurosurgery (PPC)Neurology(FO-MCB-C)andClinicalPharmacology(CB-C)UniversityHospitalofToulouseToNIC(FO-MCB-C)ToulouseNeuroimagingCenterUniversityofToulouseInserm UPS France Department of Neurosurgery (J Vesper) UniversitatsklinikumDusseldorf Germany Departments of Neurosurgery (SD) and Neurology (DM) Rouen University Hospital and University ofRouen INSERM U1239 (DM) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Mont-Saint-Aignan Service de Neurologie (P Damier P Derkinderen) CHU Nantes HopitalLaennec FranceParacelsus-Elena-KlinikKassel (FS-DCT)DepartmentofNeurosurgery (CT)UniversityMedicalCenterGottingenDivisionofFunctionalandRestorativeNeurosurgeryandCentre for IntegrativeNeuroscience (AG) Tubingen Abteilung fur Neurologie (TW) Reha-Zentrum Bad Gogging Passauer Wolf Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research (DW)Universityof TubingenDivisionofStereotactic andFunctionalNeurosurgery (MOP) UniversityMedical Center FreiburgGermanyDepartmentsof Functional andStereotacticNeurosurgery andRadiosurgery (J-MR) and Neurology (TW) Timone University Hospital INSERMMarseille Institut des Sciences Cognitives Marc Jeannerod (ST) CNRS UMR 5229 Universite de Lyon Centre Expert Parkinson (ST) Service deNeurologieCHopitalNeurologiquePierreWertheimerHospicesCivilsdeLyonBronDepartmentofNeurosurgery (PM)UniversityHospitalofNeurologyandNeurosurgeryHospicesCivilsdeLyonUniversite deLyon Department ofNeurology (J-LH) INSERM-1402 CentreHospitalier Universitaire de Poitiers University of Poitiers France andUniversitatsklinikumGiessenundMarburg (LT) Marburg Campus Germany

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article The Article Processing Chargewas funded by Medtronic

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloading andsharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology e1109

High-frequency deep brain stimulation (DBS) of the sub-thalamic nucleus (STN) is a powerful treatment in selectedpatients with Parkinson disease (PD) and levodopa-inducedmotor complications The benefit of STN-DBS has first beenshown in advanced PD with severe motor fluctuations anddyskinesia1ndash3 but more recently improvement of quality of life(QOL) and motor function have been shown with STN-DBSat an earlier stage4ndash6 The EARLYSTIM study6 addressed STN-DBS in patients with PD under 61 years of age who had a good(ie ge50) response to levodopa but had had motor com-plications for up to 3 years (mean 15 plusmn 08 SD years) In-tentionally permissive inclusion criteria were chosen thatallowed a rather broad population of patients with PD withearly motor complications to be included This was decided toenable recruitment of a large cohort and to build a studypopulation from which one would be able to draw conclusionsfor a clinical population of a reasonably broad range

This however resulted in a study population of patients withPD with a range from early mild complications to moderatelysevere and advancedmotor complications close to those for theconventional indication for DBS Therefore the question cameup whether the beneficial effect of DBS in the EARLYSTIMcohort was (mainly or only) driven by a subgroup of the entirepopulation ie the relatively advanced patients Doubts wereuttered by critics of the study whether patients with mildermotor complications would benefit from DBS Indeed it ispossible that the more advanced patients contributed more tothe overall beneficial effect of DBS found in the study thanpatients with very mild and early motor complications

We therefore performed subgroup analyses to understand theeffects of DBS in function of different variables prone to berelated to outcome of STN-DBS In particular the relativecontributions of age duration of disease and severity of dis-ease to the effect of DBS on QOL were analyzed

MethodsThe EARLYSTIM study56 was a prospective randomizedstudy comparing STN-DBS with best medical treatment(BMT) to BMT alone over 2 yearsrsquo follow-up with QOLmeasured with 39-item Parkinsonrsquos Disease Questionnairesummary index (PDQ-39-SI) as the primary endpoint Theprotocol and statistical plan of the main study are availableat nejmorgdoisuppl101056NEJMoa1205158suppl_filenejmoa1205158_protocolpdf Hypotheses of predict-ing factors for outcome were formulated before secondary

analyses were carried out Baseline characteristics including agedisease duration duration of motor complications (motor fluc-tuations and dyskinesia) severity of motor parkinsonian signsldquooffrdquo and ldquoonrdquo medication as measured with the Unified Par-kinsonrsquos Disease Rating Scale (UPDRS) motor part (III) se-verity of motor complications (UPDRS-IV) levodopa responseand baseline QOL (PDQ-39-SI) were expected to contribute tothe outcome of QOL To control for contribution of cognitionand mood to the outcome in QOL the baseline ratings for theMattis Dementia Rating Scale (MDRS) the Beck DepressionInventory (BDI) and the Montgomery-Aringsberg DepressionRating Scale (MAringDRS) were also analyzed as potential pre-dictors for change on QOL Univariate linear regression anal-yses of these baseline characteristics vs the change in QOL(PDQ-39-SI) were conducted p Values le005 were consideredstatistically significant and no adjustments were made for mul-tiple comparisons A multivariate linear regression analysis ofthe STN-DBS group was then performed including the factorswith a p lt 025 in the univariate analysis

A post hoc subgroup analysis was performed for the correla-tion of baseline PDQ-39-SI with the change in PDQ-39-SIover the 2 years using 4 subgroups of baseline PDQ-39-SI(lt15 15ndash30 30ndash45 gt45)

Data availability statement andprotocol standardsThe study protocol and statistical plan is available atnejmorgdoisuppl101056NEJMoa1205158suppl_filenejmoa1205158_protocolpdf Datawill not be availableon the web Researchers can submit proposals for collaborativestudies The study has been approved by the Kiel and ParisUniversity ethics committees The trial is registered at Clin-icalTrialsgov number NCT00354133

ResultsThe change inQOL over the 2 years correlated with the baselinevalue of the PDQ-39-SI in a regressionmodel for each treatmentgroup (STN-DBS p lt 0001 medical group p lt 0001) How-ever this effect was more pronounced among patients who weretreated with STN-DBS than in patients in the medical controlgroup (p = 00262 for interaction) (figure 1)

If baseline PDQ-39-SI was used to define categories ofseverity of impairment due to PD patients with very mildimpairment of QOL ie PDQ-39-SI values under 15 asa group did not benefit from STN-DBS as compared to

GlossaryBDI = Beck Depression Inventory BMT = best medical treatment DBS = deep brain stimulation MAringDRS = Montgomery-Aringsberg Depression Rating Scale MDRS = Mattis Dementia Rating Scale PD = Parkinson disease PDQ-39-SI = 39-itemParkinsonrsquos Disease Questionnaire summary index QOL = quality of life STN = subthalamic nucleus UPDRS = UnifiedParkinsonrsquos Disease Rating Scale

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patients in the control group with best medical treatmentalone However in this group patients with a very favorableas well as unfavorable outcome in terms of PDQ-39-SI werefound For the other categories with PDQ-39-SI ratings gt15at baseline STN-DBS resulted in better QOL than bestmedical treatment alone (figure 2) The change from base-line to 5 12 and 24 months for each patient with a change ateach point (n = 241251) by treatment group is shown infigure 3

The change of QOL over the study duration of 2 years wasindependent of age duration of PD and duration of motorcomplications (motor fluctuations dyskinesia) at baseline ina regression model This was the case when analyzed sepa-rately by treatment group as well as in a multiple regressionmodel including allocation to the treatment group

The change of QOL over the 2 years was also independentof the severity of parkinsonian motor signs in the condition

Figure 1 Correlation between 39-item Parkinsonrsquos Disease Questionnaire summary index (PDQ-39-SI) at baseline andchange to 24 months

The relation between PDQ-39-SI at baseline and the improvement PDQ-39-SI between baseline and 24months is shown The correlation ismore pronouncedfor the deep brain stimulation (DBS) group than for the best medical treatment (BMT) group

Figure 2 39-Item Parkinsonrsquos Disease Questionnaire summary index (PDQ-39-SI) by baseline category

Four categories of PDQ-39-SI baseline values wereformed 0ndash15 15ndash30 30ndash45 and gt45 points Highervalues on the PDQ-39 scale mean worse quality of lifeThe ordinate indicates the change of PDQ-39-SI overthe 2 years of the EARLYSTIM study period negativevalues mean worsening of quality of life positive val-ues mean improvement BMT = best medical treat-ment (ie control group) DBS = deep brainstimulation of the subthalamic nucleus plus bestmedical treatment n = number of patients in eachgroup DBS vs BMT statistically significant (adjustedmodel-based p values lt005)

NeurologyorgN Neurology | Volume 92 Number 10 | March 5 2019 e1111

ldquooffrdquo and ldquoonrdquo medications as measured with the UPDRS-III and independent of the severity of levodopa-inducedcomplications measured with the UPDRS-IV as well asldquooffrdquo time at baseline This was the case when analyzedseparately by treatment group as well as in a multipleregression model including allocation to the treatmentgroup

The levodopa response of the motor score (UPDRS III) atbaseline was not predictive for the change of the QOL

outcome between baseline and 24 months in the DBS-groupor in the BMT control group

Cognitive assessment at baseline with the MDRS was notpredictive of change in QOL in either treatment groupSelf-assessment of mood using the BDI at baseline didnot predict change of the PDQ-39-SI after 2 years amongpatients in the BMT group However higher baselineratings on the BDI correlated with larger improvement ofQOL among patients with STN-DBS The same was

Figure 3 Individual 39-item Parkinsonrsquos Disease Questionnaire summary index (PDQ-39-SI) change

Change of quality of life (PDQ-39) depending on the baseline PDQ-39 (B) All data at the 3 visits (5 12 and 24months) of all patients are shown depending onthe baseline value of the PDQ-39 (left column) The response is highlighted by colors (green better red no change) Patients with higher PDQ-39 values atbaseline show a better improvement

e1112 Neurology | Volume 92 Number 10 | March 5 2019 NeurologyorgN

observed for mood assessed by the examiner as ratedwith the MAringDRS in patients with STN-DBS On theother hand lower ratings on the MAringDRS correlatedwith better improvement of the PDQ-39-SI in patientswith BMT

The multivariate regression model in patients with STN-DBSincluded 4 baseline factors with p lt 025 in the univariateanalysis PDQ-39-SI (p lt 00001) BDI (p lt 0001) MAringDRS(p = 0018) and UPDRS-III ldquooffrdquo medication (p = 0216)Only the PDQ-39-SI remained significant (p lt 00001) asa baseline predictor for change in QOL in the multivariatemodel

DiscussionThe EARLYSTIM cohort was intended to broadly representthe group of relatively young patients with PD and earlymotor complications as seen in daily practice In such a co-hort the potential for improvement may be more modestthan in more advanced PD and patientsrsquo expectations are highfor STN-DBS Weighing surgery against BMT knowledgeabout predictive factors for the improvement of QOL witheither treatment is important Moreover in view of negativeresults of STN-DBS in patients with PD before the onset ofmotor complications7 STN-DBS at a very early stage hasbeen challenged as the relative contributions of age diseaseduration and duration of presence of motor complicationshave so far not been disentangled8

QOL at baseline was positively correlated with the im-provement of the PDQ-39-SI This was true for both treat-ment groups ie patients with worse QOL at baselineimproved more over the 2 yearsrsquo study period This washowever very much more pronounced among patients withSTN-DBS than with BMT alone Baseline impairment ofQOL is therefore a reasonable aspect to consider for thedecision to treat with STN-DBS We wondered if there wasa floor effect for the benefit from STN-DBS with a minimalPD-related suffering required to have a potential advantagefrom the intervention Among patients with PDQ-39-SIratings under 15 there was as a group no difference for theoutcome in QOL between the treatment groups andpatients with STN-DBS even tended to have worse averageoutcomes However this post hoc secondary analysis mustbe taken with reserve especially since the subgroup withPDQ-39-SI ratings under 15 was very small and some indi-viduals in this group had an excellent improvement of QOLwith STN-DBS and would wrongly have been barred froma beneficial treatment if a strict cutoff level for the indicationof STN-DBS had been applied In patients with very lowbaseline ratings on the PDQ-39-SI the natural progressionof impairment of QOL may outweigh the improvementachieved by STN-DBS On the other hand some patientswith very modest impairment of their QOL seem to have lessto gain from STN-DBS If they choose to undergo neuro-surgery they may do it for the wrong reasons and have

expectations that are unrealistic Therefore they may end updisappointed with the result and show worse ratings on thePDQ-39-SI Especially thorough assessment of the reasonsto undergo neurosurgery and the expectations from STN-DBS are therefore needed if the impairment of QOL is verymodest For all other categories with higher PDQ-39-SI atbaseline STN-DBS resulted in improved QOL as comparedto best medical treatment alone

In contrast to the strong prediction of improvement of QOLby baseline PDQ-39-SI ratings the change of QOL after 2years is independent from age disease duration duration ofmotor complications and severity of motor signs and motorcomplications at baseline This finding differs from the ob-servation in more advanced PD in patients with a higher ageafter 5ndash6 months where baseline cumulative daily ldquooffrdquo timewas a predictor for improvement of the PDQ-39-SI9 andyounger age was associated with better improvement of thePDQ-810 This difference could be partly related to the longerobservation period of 2 years the different patient profile(younger age shorter disease duration at surgery) in theEARLYSTIM study and to a lower variance as a result of thenarrower inclusion criteria

The discrepancy between health-related QOL and motordisease severity at baseline as predictors for the outcome ofQOL can be explained by the individual amount of sufferingattributed to a given motor impairment Objective motorimprovement does not equal subjective improvement ofoverall disease-specific QOL11 Moreover the PDQ-39 notonly assesses motor aspects of PD but affective behavioralcognitive nonmotor and psychosocial issues are also weighedwith this instrument It is known that motor signs are not themost important determinant of QOL in patients withPD12ndash14 Indeed nonmotor aspects also strongly influence thePDQ-39-SI15 and thus contribute decisively to the changes ofQOL after STN-DBS This is likely the reason why the L-doparesponse of the UPDRS motor score at baseline is predictivefor the motor outcome1617 but not necessarily for the QOLoutcome after 2 years91819 It has been shown that patientswithout dementia with borderline preoperative cognitivescores improve less in QOL than those with better cognitiveratings20 However only patients without dementia withoutsevere depression were included in the EARLYSTIM study Itis therefore not surprising that baseline assessments of cog-nition (MDRS) and mood (BDI MAringDRS) were not pre-dictive for outcome The association of higher ratings on thedepression scales with better improvement of QOL amongSTN-DBS patients may indicate that these patients havea potential for nonmotor improvement to gain from surgeryHowever the association was present only in univariateanalyses and lost in themultivariate model in which the PDQ-39-SI baseline score dominated all other factors

An important limitation of our findings regarding general-ization is the highly selected patient population Indeed theEARLYSTIM cohort consisted of young patients under 61

NeurologyorgN Neurology | Volume 92 Number 10 | March 5 2019 e1113

with a levodopa response of at least 50 as an inclusioncriterion STN-DBS has been established as a treatment formotor symptoms in advanced PD121ndash24 Importantly theresponse of motor parkinsonian signs to levodopa is anestablished predictor of the motor outcome of STN-DBS1625

Parkinsonism that does not respond to L-dopa will not benefitfrom STN-DBS26 In other words it is not the severity of themotor signs that predicts motor outcome but their responseto L-dopa In the present study levodopa response at baselinewas not a predictor of improvement in QOL Part of the expla-nation may be related to the fact that the same objective motorsign will not lead to the same subjective suffering and in the sameway improvement of motor symptoms that do not bother a pa-tient will not lead to improvement inQOL which by definition issubjective A ceiling effect may also partly explain that no suchassociation was found among our patients with STN-DBS giventhe fact that levodopa response of at least 50 was defined as aninclusion criterion and that the operated patients in the EAR-LYSTIM study had an excellent average baseline levodopa re-sponse of 635 plusmn 162 Therefore poor QOL in patients withPD in the absence of L-dopa-responsive motor symptoms shouldnot be regarded as an indication for surgery

The relation between age disease duration and outcome maybe different in older patients and in patients with a less pro-nounced response to levodopa Better outcome of STN-DBShas been suggested among younger patients with shorterdisease duration25 and outcome among older patients hasbeen reported as unfavorable27 However these patients wereoperated at a later stage for severe advanced PD Our datacannot answer the question whether STN-DBS at an earlierstage will remain advantageous over BMT beyond the 2 yearsof the duration of the EARLYSTIM study Uncontrolled openlong-term observations on patients with STN-DBS howevershow benefits that last up to a decade28

The lack of correlations of age disease duration and diseaseseverity with the change of QOL after STN-DBS leaves onlybaseline ratings of the PDQ-39-SI as a predictor for change ofQOL All patient groups above 15 points of PDQ-39-SI atbaseline have on average a clinically meaningful improvementof their QOL (figure 2) which has been estimated to be ge16points29 The majority of these patients is in the range of PDQ-39-SI gt15 (n = 114)We therefore consider it very unlikely thatthe overall favorable outcome of STN-DBS in the EAR-LYSTIM study has been driven by only a subgroup of patientscorresponding to the traditional indication with severe long-standing advanced complicated PD The major and decisiveexplanation of the improvement of QOL comes from STN-DBS ie the treatment itself across a broad range of patient ageand clinical profiles within the EARLYSTIM inclusion criteria

STN-DBS improves QOL in patients with PD and earlymotor complications who fulfil the EARLYSTIM inclusioncriteria independently of age disease duration and diseaseseverity The subjective individual suffering as measured withthe PDQ-39-SI should be taken into account as a predictive

factor for outcome when selecting patients with early motorcomplications for STN-DBS

AcknowledgmentFredy Pene (Hospital Pitie-Salpetriere Paris FranceCRA) led and coordinated communication among sitesdata review and site compliance check Anne Bissery(Hospital Pitie-Salpetriere Paris France project manager)led and coordinated communication among sites datareview and site compliance check Didier Bouton PhD(Department of Clinical Research and Development ParisFrance project manager) led and coordinated communi-cation among sites general supervision of study flowMathieu Quintin (Department of Clinical Research andDevelopment Paris France project manager) led andcoordinated communication among sites general supervi-sion of study flow Kerstin Balthasar (Coordinating Centerfor Clinical Trials Philipps University Marburg CRA) ledand coordinated communication among sites data reviewand site compliance check Elfriede Stubbs (Department ofNeurology University Hospital Cologne Germany studynurse) administrative assistance and data management inthe center Mandy Schickor (Department of NeurologyCharitendashUniversity Berlin Germany study nurse) admin-istrative assistance and data management in the centerSusanne Harnisch (Coordinating Center for Clinical TrialsPhilipps University Marburg project manager) led andcoordinated communication among sites general supervisionof study flow Behnaz Aminossadati (Coordinating Center forClinical Trials Philipps University Marburg data managementassistance) data review and plausibility checks Valerie Stoker(Medtronic Neurological Minneapolis MN project man-ager) led and coordinated communication among coordina-tors general supervision of study flow

Study fundingThis study was funded by grants from the German Ministry ofResearch (Klinische Studien 01KG0502) and the French Pro-grammeHospitalier de Recherche CliniqueNational (P050909)and by Medtronic

DisclosureW Schuepbach is a consultant for Medtronic Boston Sci-entific and Aleva has served on advisory boards for Ipsenand Merz Pharma received speakerrsquos honoraria from Aller-gan and Boston Scientific and has received unrestricted re-search grants from Actelion Boston Scientific andMedtronic L Tonder is employed by Medtronic Inc ASchnitzler has received lecture fees from AbbottSJM Bos-ton Scientific Medtronic and AbbVie and has been servingas a consultant for AbbottSJM and is a government em-ployee and receives through his institution funding for hisresearch from the German Research Council the GermanMinistry of Education and Research P Krack received grantsand personal fees from Medtronic Boston Scientific andUCB and grants from St Jude Medical France Edmond J ampLily Safra Foundation French Ministry of Health (PHRC)

e1114 Neurology | Volume 92 Number 10 | March 5 2019 NeurologyorgN

INSERM (French National Institute of Health and Researchin Medicine) France Parkinson Swiss National ScienceFoundation Roger De Spoelberch Foundation Centre Na-tional Recherche Scientifique Orkyn Homeperf and Ber-tarelli Foundation J Rau A Hartmann T Halbig and FPineau report no disclosures relevant to the manuscript AFalk has received lecture fees fromMedtronic L Paschen hasreceived lecture fees fromMedtronic S Paschen has receivedlecture fees from Medtronic travel grants from Desitin andtravel and educational grants from AbbVie and Boston Sci-entific J Volkmann reports grants and personal fees fromMedtronic grants and personal fees from Boston Scientificand personal fees from St Jude H Dafsari received grantsfrom the Thiemann Foundation the Koeln Fortune Pro-gram and the Felgenhauer Foundation and honoraria fromBoston Scientific and Medtronic M Barbe received speakershonoraria from Medtronic GE Medical UCB and St Judeand research funding from Medtronic and Boston ScientificG Fink serves as an editorial board member of severaljournals and receives royalties from Thieme and Springer andspeaking honoraria from Bayer Desitin Forum fur medi-zinische Fortbildung GmbH and Novartis A Kuhn has re-ceived lecture fees from Boston Scientific Medtronic andAbbott and has been serving as a consultant for Boston Sci-entific is a government employee and receives through herinstitution funding for her research from the German Re-search Council and the German Ministry of Education andResearch A Kupsch reports consultancy from Medtronicand speaking honoraria from Allergan Boehringer Ingel-heim Ipsen Pharma Medtronic Merck Merz Pharmaceut-icals St Jude and UCB and received grants from theGerman Research Council German Ministry of Educationand Research and the German Parkinson Foundation GSchneider has received lecture fees from Medtronic andtravel grants from Abbott and Boston Scientific E Seigneuretreports no disclosures relevant to the manuscript V Fraixreceived honoraria from AbbVie France as a scientific con-sultant A Kistner and P Chaynes report no disclosuresrelevant to the manuscript F Ory-Magne reports serving asadvisory board member for Aguettant AbbVie and Orkynand received travel grants from AbbVie Orkyn HomeperfAguettant Actelion and Merz C Brefel-Courbon reportsgrants from CHU de Toulouse France-Parkinson Associa-tion and ProgrammeHospitalier de Recherche Clinique andhas been serving as advisory board member for Zambon andas a consult for Teva UCB Aguettant AbbVie and Orkyn JVesper reports receiving consulting fees from Abbott BostonScientific and ATI and received research grants from Abbottand MDT and travel grants from Abbott and Boston Scien-tific L Wojtecki reports receiving consulting fees and lecturefees from Medtronic S Derrey and D Maltete report nodisclosures relevant to the manuscript P Damier receivedhonoraria from serving on the scientific advisory board ofCatapult (UK) and from Novartis and Teva for conferencesand holds some stock options from BampA Therapeutics(France) P Derkinderen serves as an associate editor forFrontiers in Neurodegeneration and has received research

support from France Parkinson and the Michael J FoxFoundation for Parkinsonrsquos Research F Sixel-Doring hasreceived honoraria for lectures and educational activitiesfrom AbbVie Desitin Grunenthal Licher MT MedtronicUCB Weser GmbH Asklepios Kliniken Klinikum BadHersfeld Klinikum Darmstadt Conventus Con-gressmanagement and Suazio congress participation andtravel costs were sponsored by AbbVie and Licher MT CTrenkwalder received grants from the Michael J Fox Foun-dation and the European Commission Horizon 2020ldquoPropag-ageingrdquo Mundipharma and UCB funding forconsultancy from Novartis Benevolent Grunenthal Bri-tannia and Vifor and speakers fee from UCB GrunenthalAbbVie and Britannia A Gharabaghi is funded by the Ger-man Federal Ministry of Education and Research (BMBF13GW0119B and BMBF 13GW0214B) and the Baden-Wuerttemberg Foundation (NEU005) and receives researchsupport from Medtronic Boston Scientific and Abbott TWachter received speaker honoraria from Bial-Portela amp CaSA and UCB Pharma GmbH D Weiss is supported by theGerman Research Foundation (DFG WE53751-3) andreceives research support speakers honoraria and travelgrants from Medtronic Boston Scientific and Abbott MPinsker received speaker fees from Medtronic J Regis hasreceived honoraria fromMedtronic and a research grant fromElekta T Witjas has received honoraria from UCB AbbVieTeva and Medtronic and has received a research grant fromthe French Ministry of Health S Thobois reports grantsfrom Fondation pour la Recherche Medicale and FondationNeurodis grants from France Parkinson personal fees fromUCB Novartis Teva St Jude and Aguettant and travel andcongress grants from Zambon and AbbVie P Mertensreports consultancy for Medtronic K Knudsen and CSchade-Brittinger report no disclosures relevant to themanuscript J Houeto has received research grant fromAgence National de la Recherche Association France Parkin-son and AbbVie and fees for lectures and consultancies fromMedtronic Zambon AbbVie and Lundbeck Y Agid receivesfunds from Servier and the Institut du Cerveau et de la MoelleEpiniere M Vidailhet reports no disclosures relevant to themanuscript L Timmerman received funds from MedtronicBoston Scientific Sapiens St Jude Medical Bayer HealthcareUCB and Archimedes Pharma grants from MampU MullerFoundation NBIA Foundation and German ParkinsonFoundation and payments for lectures from TEVA LundbeckBracco Gianni PR Medas UCB Desitin Boehringer GSKEumecom and Orion Pharm G Deuschl received lecture feesfrom Boston Scientific and has been serving as a consultant forBoston Scientific received royalties from Thieme is a govern-ment employee and receives through his institution fundingfor his research from the German Research Council the Ger-man Ministry of Education and Research and Medtronic Goto NeurologyorgN for full disclosures

Publication historyReceived by NeurologyMay 10 2018 Accepted in final form November4 2018

NeurologyorgN Neurology | Volume 92 Number 10 | March 5 2019 e1115

Appendix 1 Authors

Name Location Role Contribution

WM MichaelSchuepbachMD

Assistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere CentredrsquoInvestigation Clinique 1422Departement de NeurologieHopital Pitie-Salpetriere ParisFrance Institute of NeurologyKonolfingen SwitzerlandDepartment of NeurologyUniversity Hospital Bern andUniversity of Bern Switzerland

Author Designed andconceptualizedstudy major role inthe acquisition ofdata drafted thefirst version of themanuscript

Lisa Tonder Medtronic Minneapolis MN Author Analysis orinterpretationof thedata

AlfonsSchnitzlerMD PhD

Institute of ClinicalNeuroscience amp MedicalPsychology and Department ofNeurology Medical FacultyHeinrich-Heine-UniversityDusseldorf Germany

Author Designed andconceptualizedstudy major role inthe acquisition ofdata drafted themanuscript forintellectual content

Paul KrackMD PhD

Movement Disorder UnitNeurology CHUGrenoble AlpesUniversite de Grenoble AlpesGrenoble Institut desNeurosciences GIN andInserm U1216 FranceDepartment of ClinicalNeurosciences (Neurology)Faculty of Medicine Universityof Geneva Switzerland

Author Designed andconceptualizedstudy major role inthe acquisition ofdata drafted themanuscript forintellectual content

Joern Rau Coordinating Center for clinicaltrials of the Philipps Universityof Marburg Germany

Author Designed andconceptualizedstudy analysis orinterpretationof thedata drafted themanuscript forintellectual content

AndreasHartmannMD PhD

Assistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere CentredrsquoInvestigation Clinique 1422Departement de NeurologieHopital Pitie-Salpetriere ParisFrance

Author Major role in theacquisition of data

Thomas DHalbig MD

Assistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere CentredrsquoInvestigation Clinique 1422Departement de NeurologieHopital Pitie-Salpetriere ParisFrance Klinik fur NeurologieCampus VirchowCharitendashUniversitatsmedizinBerlin Germany

Author Major role in theacquisition of data

Fanny PineauPhD

Assistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere CentredrsquoInvestigation Clinique 1422Departement de NeurologieHopital Pitie-Salpetriere ParisFrance

Author Major role in theacquisition of data

Andrea FalkMD

Neurochirurgische Klinik imNeurozentrum Christian-Albrechts-Universitat KielGermany

Author Major role in theacquisition of data

Appendix 1 (continued)

Name Location Role Contribution

LauraPaschen MD

Neurologische Klinik imNeurozentrum Christian-Albrechts-Universitat KielGermany

Author Major role in theacquisition of data

StephenPaschen MD

Neurologische Klinik imNeurozentrum Christian-Albrechts-Universitat KielGermany

Author Major role in theacquisition of data

JensVolkmannMD PhD

Neurologische Klinik imNeurozentrum Christian-Albrechts-Universitat KielNeurologische Klinik undPoliklinik UniversitatsklinikumWurzburg Germany

Author Major role in theacquisition of data

Haidar SDafsari MD

Department of NeurologyUniversity Hospital CologneGermany

Author Major role in theacquisition of data

Michael TBarbe MDPhD

Department of NeurologyUniversity Hospital CologneGermany

Author Major role in theacquisition of data

Gereon RFink MD PhD

Department of NeurologyUniversity Hospital CologneResearch Centre Julich INM-3Germany

Author Major role in theacquisition of data

Andrea KuhnMD

Klinik fur Neurologie CampusVirchow CharitendashUniversitatsmedizin BerlinGermany

Author Major role in theacquisition of data

AndreasKupsch MDPhD

Klinik fur Neurologie CampusVirchowCharitendashUniversitatsmedizinBerlin Germany Praxis Kupsch

Author Major role in theacquisition of data

Gerd-HSchneiderMD PhD

Klinik fur NeurochirurgieCampus VirchowCharitendashUniversitatsmedizinBerlin Germany

Author Major role in theacquisition of data

EricSeigneuretMD

Service de NeurochirurgieHopital Michallon CentreHospitalo-UniversitaireGrenoble France

Author Major role in theacquisition of data

Valerie FraixMD

Grenoble Institut desNeurosciences GIN INSERMU1216 Universite GrenobleAlpes Service de NeurologieHopital Michallon CentreHospitalo-UniversitaireGrenoble France

Author Major role in theacquisition of data

AndreaKistner MSc

Grenoble Institut desNeurosciences GIN INSERMU1216 Universite GrenobleAlpes France

Author Major role in theacquisition of data

P PatrickChaynes MDPhD

Department of NeurosurgeryUniversity Hospital of ToulouseFrance

Author Major role in theacquisition of data

Fabienne Ory-Magne MD

Department of NeurologyUniversity Hospital of ToulouseToNIC Toulouse NeuroimagingCenter University of ToulouseInserm UPS France

Author Major role in theacquisition of data

ChristineBrefelCourbon MDPhD

Department of NeurologyUniversity Hospital of ToulouseDepartment of NeurologyDepartment of ClinicalPharmacology UniversityHospital of Toulouse ToNICToulouse Neuroimaging CenterUniversity of Toulouse InsermUPS France

Author Major role in theacquisition of data

e1116 Neurology | Volume 92 Number 10 | March 5 2019 NeurologyorgN

Appendix 1 (continued)

Name Location Role Contribution

Jan VesperMD PhD

Department of NeurosurgeryUniversitatsklinikumDusseldorf Germany

Author Major role in theacquisition of data

Lars WojteckiMD PhD

Institute of ClinicalNeuroscience amp MedicalPsychology and Department ofNeurology Medical FacultyHeinrich-Heine-UniversityDusseldorf Germany

Author Major role in theacquisition of data

StephaneDerrey MD

Department of NeurosurgeryRouen University Hospital andUniversity of Rouen France

Author Major role in theacquisition of data

DavidMaltete MDPhD

Department of NeurologyRouen University Hospital andUniversity of Rouen INSERMU1239 Laboratory of Neuronaland NeuroendocrineDifferentiation andCommunication Mont-Saint-Aignan France

Author Major role in theacquisition of data

PhilippeDamier MDPhD

Service de Neurologie HopitalLaennec CHU Nantes France

Author Major role in theacquisition of data

PascalDerkinderenMD PhD

Service de Neurologie HopitalLaennec CHU Nantes France

Author Major role in theacquisition of data

FriderikeSixel-DoringMD

Paracelsus-Elena-Klinik KasselGermany

Author Major role in theacquisition of data

ClaudiaTrenkwalderMD PhD

Paracelsus-Elena-Klinik KasselGermany Department ofNeurosurgery UniversityMedical Center GottingenGermany

Author Major role in theacquisition of data

AlirezaGharabaghiMD PhD

Division of Functional andRestorative Neurosurgery andCentre for IntegrativeNeuroscience TubingenGermany

Author Major role in theacquisition of data

TobiasWachter MD

Abteilung fur Neurologie Reha-Zentrum Bad Gogging PassauerWolf Germany

Author Major role in theacquisition of data

Daniel WeissMD PhD

Department forNeurodegenerative Diseasesand Hertie Institute for ClinicalBrain Research University ofTubingen Germany

Author Major role in theacquisition of data

Marcus OPinsker MDPhD

Division of Stereotactic andFunctional NeurosurgeryUniversity Medical CenterFreiburg Germany

Author Major role in theacquisition of data

Jean-MarieRegis MDPhD

Department of Functional andStereotactic Neurosurgery andRadiosurgery TimoneUniversity Hospital INSERMMarseille France

Author Major role in theacquisition of data

TatianaWitjas MDPhD

Department of NeurologyTimone University HospitalUMR 7289 CNRS MarseilleFrance

Author Major role in theacquisition of data

StephaneThobois MDPhD

Institut des Sciences CognitivesMarc Jeannerod CNRS UMR5229 Universite de Lyon CentreExpert Parkinson Service deNeurologie C HopitalNeurologique PierreWertheimer Hospices Civils deLyon Bron France

Author Major role in theacquisition of data

Appendix 1 (continued)

Name Location Role Contribution

PatrickMertens MDPhD

Department of NeurosurgeryUniversity Hospital of Neurologyand Neurosurgery HospicesCivils de Lyon Universite deLyon France

Author Major role in theacquisition of data

KarinaKnudsen MD

Neurologische Klinik imNeurozentrum Christian-Albrechts-Universitat KielGermany

Author Designed andconceptualizedstudy major role inthe acquisition ofdata

CarmenSchade-Brittinger

Coordinating Center for Clinicaltrials of the Philipps Universityof Marburg Germany

Author Designed andconceptualizedstudy revised themanuscript forintellectual content

Jean-LucHoueto MDPhD

Department of NeurologyINSERM-1402 CentreHospitalier Universitaire (CHU)de Poitiers University ofPoitiers France

Author Designed andconceptualizedstudy major role inthe acquisition ofdata revised themanuscript forintellectual content

YvesAgidMDPhD

Departement de NeurologieCentre drsquoInvestigation Clinique1422 Hopital Pitie-SalpetriereAssistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere Paris France

Author Design andconceptualizedstudy

MarieVidailhet MDPhD

Departement de NeurologieCentre drsquoInvestigation Clinique1422 Hopital Pitie-SalpetriereAssistance Publique Hopitauxde Paris Institut National deSante et en RechercheMedicaleInstitut du Cerveau et de laMoelle Epiniere Paris France

Author Designed andconceptualizedstudy revised themanuscript forintellectual content

LarsTimmermannMD PhD

Department of NeurologyUniversity Hospital CologneUniversitatsklinikum GiessenundMarburg Marburg CampusGermany

Author Designed andconceptualizedstudy major role inthe acquisition ofdata revised themanuscript forintellectual content

GuntherDeuschl MDPhD

Neurologische Klinik imNeurozentrum Christian-Albrechts-Universitat KielGermany

Author Designed andconceptualizedstudy major role inthe acquisition ofdata drafted themanuscript forintellectual content

NeurologyorgN Neurology | Volume 92 Number 10 | March 5 2019 e1117

Appendix 2 Coinvestigators

Name Location Role Contribution

VirginieCzerneckiPhD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

HelkeHesekampMD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

NiklausMeier MD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

VelinaNegovanskaPhD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

Marie-LaureWelter MDPhD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

Jean-ChristopheCorvol MDPhD

Federation ofNeurologyHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

PhilippeCornu MDPhD

Department ofNeurosurgeryHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Contribution todesign andconceptualizationof the study

SoledadNavarro MD

Department ofNeurosurgeryHospital Pitie-Salpetriere ParisFrance

Siteinvestigator

Data collection

BettinaMoller

Department ofNeurologyChristian-Albrechts-University KielGermany

Psychologist Psychologicalassessmentsdata collection

AdelheidNebel

Department ofNeurologyChristian-Albrechts-University KielGermany

Siteinvestigator

Data collection

Karsten WittMD PhD

Department ofNeurologyChristian-Albrechts-University KielGermany

Siteinvestigator

Data collection

Jan RaethjenMD PhD

Department ofNeurologyChristian-Albrechts-University KielGermany

Siteinvestigator

Data collection

Appendix 2 (continued)

Name Location Role Contribution

MaximilianMehdornMD PhD

Department ofNeurosurgeryChristian-Albrechts-University KielGermany

Director ofclinicneurosurgeryin Kiel

Data collection

Ingo GMeister MDPhD

Department ofPsychiatryUniversityHospital CologneGermany

Siteinvestigator

Data collection

Jens KuhnMD PhD

Department ofPsychiatryUniversityHospital CologneGermany

Siteinvestigator

Data collection

Josef KesslerMD PhD

Department ofNeurologyUniversityHospital CologneGermany

Siteinvestigator

Data collection

DoreenGruber

Department ofNeurologyCharite UniversityBerlin Germany

Siteinvestigator

Data collection

KatharinaFaust MDPhD

Department ofNeurologyCharite UniversityBerlin Germany

Siteinvestigator

Data collection

StephanChabardesMD

Department ofNeurosurgeryHospital MichallonUniversityGrenoble France

Siteinvestigator

Data collection

Pierre PollakMD PhD

Department ofNeurology andPsychiatryUniversityGrenoble France

Siteinvestigator

Data collection

Oliver RascolMD PhD

Department ofPharmacologyUniversityHospital ToulouseFrance

Siteinvestigator

Data collection

ChristopheArbus

Department ofPsychiatryUniversityHospital ToulouseFrance

Siteinvestigator

Data collection

Lola Danet Department ofNeurologyUniversityHospital ToulouseFrance

Siteinvestigator

Data collection

RomainLefaucheur

Department ofNeurology RouenUniversity Hospitaland University ofRouen France

Siteinvestigator

Data collection

IsabelleBenatru

Department ofNeurologyUniversity ofPoitiers France

Siteinvestigator

Data collection

e1118 Neurology | Volume 92 Number 10 | March 5 2019 NeurologyorgN

References1 Limousin P Krack P Pollak P et al Electrical stimulation of the subthalamic nucleus

in advanced Parkinsonrsquos disease N Engl J Med 19983391105ndash11112 Lagrange E Krack P Moro E et al Bilateral subthalamic nucleus stimulation

improves health-related quality of life in PD Neurology 2002591976ndash19783 Deuschl G Schade-Brittinger C Krack P et al A randomized trial of deep-brain

stimulation for Parkinsonrsquos disease N Engl J Med 2006355896ndash9084 Schupbach M Gargiulo M Welter ML et al Neurosurgery in Parkinson disease

a distressed mind in a repaired body Neurology 2006661811ndash18165 Deuschl G Schupbach M Knudsen K et al Stimulation of the subthalamic nucleus at

an earlier disease stage of Parkinsonrsquos disease concept and standards of the EAR-LYSTIM-study Parkinsonism Relat Disord 20131956ndash61

6 Schuepbach WM Rau J Knudsen K et al Neurostimulation for Parkinsonrsquos diseasewith early motor complications N Engl J Med 2013368610ndash622

7 Charles D Konrad PE Neimat JS et al Subthalamic nucleus deep brain stimulation inearly stage Parkinsonrsquos disease Parkinsonism Relat Disord 201420731ndash737

8 A controlled trial of rasagiline in early Parkinson disease the TEMPO Study ArchNeurol 2002591937ndash1943

9 Daniels C Krack P Volkmann J et al Is improvement in the quality of life aftersubthalamic nucleus stimulation in Parkinsonrsquos disease predictable Mov Disord2011262516ndash2521

10 Dafsari HS Reker P Silverdale M et al Subthalamic stimulation improves quality oflife of patients aged 61 years or older with short duration of Parkinsonrsquos diseaseNeuromodulation 201821532ndash540

11 Martinez-Martin P Valldeoriola F Tolosa E et al Bilateral subthalamic nucleus stimulationand quality of life in advanced Parkinsonrsquos disease Mov Disord 200217372ndash377

12 Schrag A Jahanshahi M Quinn N How does Parkinsonrsquos disease affect quality of life Acomparison with quality of life in the general population Mov Disord 2000151112ndash1118

13 Soh SE Morris ME McGinley JL Determinants of health-related quality of life inParkinsonrsquos disease a systematic review Parkinsonism Relat Disord 2011171ndash9

14 Fereshtehnejad SM Shafieesabet M Farhadi F et al Heterogeneous determinants ofquality of life in different phenotypes of Parkinsonrsquos disease PLoS One 201510e0137081

15 Martinez-Martin P Rodriguez-Blazquez C Kurtis MM Chaudhuri KR Group NVThe impact of non-motor symptoms on health-related quality of life of patients withParkinsonrsquos disease Mov Disord 201126399ndash406

16 Charles PD Van Blercom N Krack P et al Predictors of effective bilateral sub-thalamic nucleus stimulation for PD Neurology 200259932ndash934

Appendix 2 (continued)

Name Location Role Contribution

Olivier Colin Department ofNeurologyUniversity ofPoitiers France

Siteinvestigator

Data collection

SoleneAnsquer

Department ofNeurophysiologyUniversity ofPoitiers France

Siteinvestigator

Data collection

Stefan JGroiss

Department ofNeurologyInstitute of ClinicalNeuroscience andMedicalPsychologyHeinrich-Heine-UniversityDusseldorfGermany

Siteinvestigator

Data collection

Saskia ElbenPhD

Department ofNeurologyInstitute of ClinicalNeuroscience andMedicalPsychologyHeinrich-Heine-UniversityDusseldorfGermany

Psychologist Data collectionpsychologicaltesting

ChristianHartmannMD PhD

Department ofNeurologyInstitute of ClinicalNeuroscience andMedicalPsychologyHeinrich-Heine-UniversityDusseldorfGermany

Siteinvestigator

Data collection

MartinSudmeyerMD PhD

Department ofNeurologyInstitute of ClinicalNeuroscience andMedicalPsychologyHeinrich-Heine-UniversityDusseldorfGermany

Siteinvestigator

Data collection

FlorianAmtage MDPhD

Department ofNeurologyUniversity HospitalFreiburg Germany

Siteinvestigator

Data collection

RejkoKrueger MDPhD

Department ofNeurologyUniversity ofTubingenGermany

Siteinvestigator

Data collectiondesign andconceptualizationof geneticsubstudy

SeverineLedily

Department ofNeurologyHospital LaennecUniversity NantesFrance

Siteinvestigator

Data collection

AnneSauvaget

Department ofPsychiatryHospital LaennecUniversity NantesFrance

Siteinvestigator

Data collection

Appendix 2 (continued)

Name Location Role Contribution

WenkeSchmidt

Paracelsus-Elena-Klinik KasselGermany

Psychologist Psychologicalassessmentsdata collection

AlexandroEusebio MDPhD

Department ofNeurologyHospital TimoneMarseille France

Siteinvestigator

Data collection

Jean PhilippeAzulay MDPhD

Department ofNeurologyHospital TimoneMarseille France

Siteinvestigator

Data collection

GustavoPolo PhD

Department ofNeurosurgeryUniversity Lyon 1France

Siteinvestigator

Data collection

Serge PintoPhD

Department ofLaboratory Wordand LanguageUniversity Aix-Marseille France

Siteinvestigator

Data collection

JohannesLevin MDPhD

Department ofNeurologyUniversity Munich-GroszlighadernMunich Germany

Siteinvestigator

Data collection

Wolfgang HOertel MDPhD

Department ofNeurologyPhilipps-UniversityMarburg Germany

BMTcommittee

Qualitymanagement ofthe BMT

NeurologyorgN Neurology | Volume 92 Number 10 | March 5 2019 e1119

17 Kleiner-FismanGHerzog J FismanDN et al Subthalamic nucleus deep brain stimulationsummary and meta-analysis of outcomes Mov Disord 200621(suppl 14)S290ndashS304

18 Smeding HM Speelman JD Huizenga HM Schuurman PR Schmand B Predictorsof cognitive and psychosocial outcome after STN DBS in Parkinsonrsquos diseaseJ Neurol Neurosurg Psychiatry 201182754ndash760

19 Abboud H Genc G Thompson NR et al Predictors of functional and quality of lifeoutcomes following deep brain stimulation surgery in Parkinsonrsquos disease patientsdisease patient and surgical factors Parkinsons Dis 201720175609163

20 Witt K Daniels C Krack P et al Negative impact of borderline global cognitive scoreson quality of life after subthalamic nucleus stimulation in Parkinsonrsquos disease J NeurolSci 2011310261ndash266

21 Krack P Batir A Van Blercom N et al Five-year follow-up of bilateral stimulationof the subthalamic nucleus in advanced Parkinsonrsquos disease N Engl J Med 20033491925ndash1934

22 Weaver FM Follett K Stern M et al Bilateral deep brain stimulation vs best medicaltherapy for patients with advanced Parkinson disease a randomized controlled trialJAMA 200930163ndash73

23 Follett KA Weaver FM Stern M et al Pallidal versus subthalamic deep-brain stim-ulation for Parkinsonrsquos disease N Engl J Med 20103622077ndash2091

24 Williams A Gill S Varma T et al Deep brain stimulation plus best medical therapyversus best medical therapy alone for advanced Parkinsonrsquos disease (PD SURG trial)a randomised open-label trial Lancet Neurol 20109581ndash591

25 Welter ML Houeto JL Tezenas du Montcel S et al Clinical predictive factors ofsubthalamic stimulation in Parkinsonrsquos disease Brain 2002125575ndash583

26 Krack P Dowsey PL Benabid AL et al Ineffective subthalamic nucleus stimulation inlevodopa-resistant postischemic parkinsonism Neurology 2000542182ndash2184

27 Russmann H Ghika J Villemure JG et al Subthalamic nucleus deep brain stimulationin Parkinson disease patients over age 70 years Neurology 2004631952ndash1954

28 Deuschl G Agid Y Subthalamic neurostimulation for Parkinsonrsquos disease withearly fluctuations balancing the risks and benefits Lancet Neurol 2013121025ndash1034

29 Shulman LM Gruber-Baldini AL Anderson KE Fishman PS Reich SG Weiner WJThe clinically important difference on the Unified Parkinsonrsquos Disease Rating ScaleArch Neurol 20106764ndash70

e1120 Neurology | Volume 92 Number 10 | March 5 2019 NeurologyorgN

DOI 101212WNL0000000000007037201992e1109-e1120 Published Online before print February 8 2019Neurology

WM Michael Schuepbach Lisa Tonder Alfons Schnitzler et al Quality of life predicts outcome of deep brain stimulation in early Parkinson disease

This information is current as of February 8 2019

ServicesUpdated Information amp

httpnneurologyorgcontent9210e1109fullincluding high resolution figures can be found at

References httpnneurologyorgcontent9210e1109fullref-list-1

This article cites 29 articles 6 of which you can access for free at

Citations httpnneurologyorgcontent9210e1109fullotherarticles

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httpnneurologyorgcgicollectionparkinsons_disease_parkinsonismParkinsons diseaseParkinsonismfollowing collection(s) This article along with others on similar topics appears in the

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nextAn erratum has been published regarding this article Please see

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ISSN 0028-3878 Online ISSN 1526-632XWolters Kluwer Health Inc on behalf of the American Academy of Neurology All rights reserved Print1951 it is now a weekly with 48 issues per year Copyright Copyright copy 2019 The Author(s) Published by

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

Disputes amp Debates Editorsrsquo ChoiceSteven Galetta MD FAAN Section Editor

Reader response Practice guideline update recommendationssummary Disorders of consciousness Report of the GuidelineDevelopment Dissemination and Implementation Subcommittee ofthe American Academy of Neurology the American Congress ofRehabilitation Medicine and the National Institute on DisabilityIndependent Living and Rehabilitation ResearchThanh G Phan (Clayton Australia) Udaya Seneviratne (Clayton Australia) and Henry Ma (Clayton Australia)

Neurologyreg 2019921163ndash1164 doi101212WNL0000000000007668

We read with interest the disorders of consciousness guideline1 but found issues with the rec-ommendations Some of the recommendations are classified as level A (recommendations 3 9and 11) For example ldquoWhen prognosis is poor long-term care must be discussed (level A)helliprdquo1

The references cited did not come from a randomized control trial Typically level A is based onone or more randomized control trial and is prefaced by a statement about the class of evidenceWe cannot find references to any trials on which these recommendations were made12 Can theauthors reassess the use of the level of recommendation in this guideline

Editorsrsquonote Practice guidelineupdate recommendations summaryDisorders of consciousness Report of the Guideline DevelopmentDissemination and Implementation Subcommittee of the AmericanAcademy of Neurology the American Congress of RehabilitationMedicine and the National Institute on Disability IndependentLiving and Rehabilitation ResearchIn their American Academy of Neurology (AAN) practice parameter Giacino et al pro-vided a thorough review of the available evidence pertaining to the care of patients withimpaired consciousness The expert panel provided level of recommendations (LORs)regarding the discussion of long-term care needs pain management strategies and tech-niques for neuroprognostication in patients with disorders of consciousness In response tothese consensus recommendations Phan et al highlight 1 potential limitation of the LORclassification system that was used Historically the highest LOR (level A) was affordedonly to recommendations based on 1 or more randomized clinical trials However thisrequirement was amended by the Institute of Medicine in 2011 as well as the 2011 AANClinical Guideline Practice Manual as the authors emphasize in their response After 2011a level A recommendation was permitted as long as there was strong and consistent relatedevidence and inferences could be drawn Therefore a higher LOR could be assigned torecommendations with less explicit substantiation from large randomized clinical trials Byusing this classification schema some recommendations may be generalized to patientswho are likely to benefit from such guidance

James E Siegler III MD and Steven Galetta MD

Neurologyreg 2019921163 doi101212WNL0000000000007660

NeurologyorgN Neurology | Volume 92 Number 24 | June 11 2019 1163

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited

1 Giacino JT Katz DI Schiff ND et al Practice guideline update recommendations summary disorders of consciousness report of theGuideline Development Dissemination and Implementation Subcommittee of the American Academy of Neurology the AmericanCongress of Rehabilitation Medicine and the National Institute on Disability Independent Living and Rehabilitation ResearchNeurology 201891450ndash460

2 Giacino JT Katz DI Schiff ND et al Comprehensive systematic review update summary disorders of consciousness report of theGuideline Development Dissemination and Implementation Subcommittee of the American Academy of Neurology the AmericanCongress of Rehabilitation Medicine and the National Institute on Disability Independent Living and Rehabilitation ResearchNeurology 201891461ndash470

Copyright copy 2019 American Academy of Neurology

Author response Practice guideline update recommendationssummary Disorders of consciousness Report of the GuidelineDevelopment Dissemination and Implementation Subcommittee ofthe American Academy of Neurology the American Congress ofRehabilitation Medicine and the National Institute on DisabilityIndependent Living and Rehabilitation ResearchMelissa J Armstrong (Gainesville FL) Joseph T Giacino (Boston) Douglas I Katz (Braintree MA)

Nicholas D Schiff (New York) John Whyte (Elkins Park PA) Eric J Ashman (Kalamazoo MI) Stephen Ashwal

(Loma Linda CA) Richard Barbano (Rochester NY) Flora M Hammond (Indianapolis) Steven Laureys (Liege

Belgium) Geoffrey SF Ling (Baltimore) Risa Nakase-Richardson (Tampa FL) Ronald T Seel (Richmond VA)

Stuart Yablon (Jackson MS) Thomas SD Getchius (Washington DC) and Gary S Gronseth (Kansas City KS)

Neurologyreg 2019921164 doi101212WNL0000000000007669

American Academy of Neurology (AAN) guidelines comply with the AAN InstituteBoard-approved guideline methodology referenced within the systematic reviewguideline12 Compliance is ensured by a methodologist working on each project andmultiple rounds of AAN Guideline Development Dissemination and Implementation Sub-committee review We believe that Phan et al are referencing the 2004 recommendation meth-odology3 The disorders of consciousness guideline used the 2011 AAN guideline manual asamended4 based on 2011 Institute ofMedicine (IOM) standards for evidence-based guidelines5 Inthis process recommendations are based not only on a systematic review of the evidence but also onstrongly related evidence principles of care and inferences The level of obligation for each rec-ommendation is determined by the strength of these premises and a riskndashbenefit assessment withadjustments based on outcome importance patient preference variability feasibilityavailability andpatient costs Consensus is determined by a modified Delphi voting process in accordance withprespecified rules as described in the systematic review2 This IOM-compliant approach improvesrecommendation usability The modified Delphi tables and the premise types for each recom-mendation rationale are available in the online appendices NPuborgm5ii8i (ldquorationale profilesrdquofor recommendations 3 9 and 11 are on pages 190 204 and 206 respectively)

1 Giacino JT Katz DI Schiff ND et al Practice guideline update recommendations summary disorders of consciousness report of theGuideline Development Dissemination and Implementation Subcommittee of the American Academy of Neurology the AmericanCongress of Rehabilitation Medicine and the National Institute on Disability Independent Living and Rehabilitation ResearchNeurology 201891450ndash460

2 Giacino JT Katz DI Schiff ND et al Comprehensive systematic review update summary disorders of consciousness report of theGuideline Development Dissemination and Implementation Subcommittee of the American Academy of Neurology the AmericanCongress of Rehabilitation Medicine and the National Institute on Disability Independent Living and Rehabilitation ResearchNeurology 201891461ndash470

3 American Academy of Neurology Clinical Practice Guideline Process Manual 2004 ed St Paul MN American Academy of Neurology 20044 American Academy of Neurology Clinical Practice Guideline Process Manual 2011 ed St Paul American Academy of Neurology 20115 Graham R Mancher M Miller Wolman D Greenfield S Steinberg E editors Clinical Practice Guidelines We Can Trust Washington

DC The National Academies Press 2011 In The National Academies of Sciences [online] Available at nationalacademiesorghmdReports2011Clinical-Practice-Guidelines-We-Can-Trustaspx Accessed October 12 2018

Copyright copy 2019 American Academy of Neurology

1164 Neurology | Volume 92 Number 24 | June 11 2019 NeurologyorgN

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Reader response Clinical Reasoning A 54-year-old woman withconfusion and visual disturbancesLea Pollak (Ness Ziona Israel)

Neurologyreg 2019921165 doi101212WNL0000000000007670

In the Resident amp Fellow Clinical Reasoning paper by Rossi et al1 the authors described anunusual case of Balint syndrome caused by focal nonconvulsive status epilepticus in a patientwith cirrhosis and hyponatremia I am curious about the nature of the clinical finding ldquohelliphorizontal nystagmus in all directions including on primary gazerdquo1

Horizontal nystagmus in all directions localizes to the brainstemcerebellum however in thiscase1 the lesions were parieto-occipital Hyponatremia if accompanied by hypomagnesemiawould cause a downbeat nystagmus Could the nystagmus thus be an epileptic nystagmus ofcortical origin The bilaterality of the epileptic foci might explain the bilateral direction of thenystagmus The authors describe an intermittent eye deviation on video during EEG recordingthe mechanism is therefore probably due to epileptic alternative eye deviation with quickcorrective saccades It would be interesting to know the direction of the nystagmus since thismay elucidate whether the underlying activated mechanism of the eye deviations was saccadicor pursuit Furthermore the finding of a normal optokinetic nystagmus in Balint syndrome andduring seizures is mostly unusual Also can the authors please comment on the radiologicfollow-up of this patient as the parieto-occipital T2 hyperintensities should resolve with time ifattributed to seizure activity

1 Rossi KC Brandstadter R Fields MC Leong J Shin S Clinical Reasoning a 54-year-old woman with confusion and visual disturbancesNeurology 201891363ndash367

Copyright copy 2019 American Academy of Neurology

Editorsrsquo note Clinical Reasoning A 54-year-old woman withconfusion and visual disturbancesRossi et al presented the unusual case of a 54-year-old woman with cirrhosis who de-veloped oculomotor apraxia optic ataxia impaired smooth pursuit and horizontal nys-tagmus in all directions of gaze The neuroimaging and electrographic diagnosis wasnonconvulsive status epilepticus resulting in Balint syndrome Dr Pollak also suspects anepileptic origin of the horizontal alternating nystagmus pattern given the bilateralMRI andEEG findings However Dr Pollack notes that a normal optokinetic nystagmus would beunusual during seizure activity Rossi et al attribute this to the fluctuating nature of thepatientrsquos condition and the intermittent epileptiform activity on EEG Resolution of thecortical diffusion abnormalities on MRI would also have supported seizures as the cause ofthe patientrsquos symptoms as Dr Pollak writes Unfortunately this could not be confirmed asthe patient was lost to follow-up

James E Siegler III MD and Steven Galetta MD

Neurologyreg 2019921165 doi101212WNL0000000000007671

NeurologyorgN Neurology | Volume 92 Number 24 | June 11 2019 1165

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Author response Clinical Reasoning A 54-year-old woman withconfusion and visual disturbancesKyle C Rossi (New York) Rachel Brandstadter (New York) Madeline C Fields (New York) and

Susan Shin (New York)

Neurologyreg 2019921166 doi101212WNL0000000000007672

We thank Dr Pollak for the thoughtful comments on our article1 The nature of the nystagmuswas variable over the clinical course Our earliest notes described direction-changing horizontalgaze-evoked nystagmus on left and right end gaze and primary gaze The mechanism ofepileptic nystagmus is poorly understood with most available literature being from case reportsoften reporting the fast phase of nystagmus away from the seizure focus2ndash4 Here the bilateralfoci could explain the direction changing nature of the nystagmus Of note the case wasconfounded by metabolic derangements potentially contributing to brainstem dysfunction andeye movement abnormalities Although epileptic nystagmus is possible it is difficult to con-clude with certainty

The intact optokinetic nystagmus (OKN) reflex could be related to the fluctuating nature of thesymptoms given an epileptic origin as opposed to a fixed structural origin Additionally Balohet al5 reported on the structural pathways involved in the OKN reflex suggesting a complicated2-pathway mechanism and showing that many parietal lesions do not obliterate all parts of theOKN response uniformly

Regarding follow-up imaging the patient was unfortunately lost to follow-up from a neurologyperspective the plan for follow-up imaging was not completed at our institution

1 Rossi KC Brandstadter R Fields MC Leong J Shin S Clinical Reasoning a 54-year-old woman with confusion and visual disturbancesNeurology 201891363ndash367

2 Lee SU Suh HI Choi JY et al Epileptic nystagmus a case report and systematic review Epilepsy Behav Case Rep 20142156ndash1603 Ma Y Wang J Li D Lang S Two types of isolated epileptic nystagmus case report Int J Clin Exp Med 2015813500ndash135074 Bhai S Malik AN Bakhadirov K Prasad S Alternating ictal and postictal nystagmus Neurol Clin Pract 20144522ndash5235 Baloh RW Yee RD Honrubia V Optokinetic nystagmus and parietal lobe lesions Ann Neurol 19807269ndash276

Copyright copy 2019 American Academy of Neurology

CORRECTION

Quality of life predicts outcome of deep brain stimulation in earlyParkinson diseaseNeurologyreg 2019921166 doi101212WNL0000000000007420

In the article ldquoQuality of life predicts outcome of deep brain stimulation in early Parkinsondiseaserdquo by Schuepbach et al1 published online ahead of print on February 8 2019Dr Halbigrsquos name should have included a middle initial Thomas D Halbig The correctedname appears in the March 5 issue The editorial office regrets the error

Reference1 Schuepbach WMM Tonder L Schnitzler A et al Quality of life predicts outcome of deep brain stimulation in early Parkinson disease

Neurology 201992e1109ndashe1120

1166 Neurology | Volume 92 Number 24 | June 11 2019 NeurologyorgN

Author disclosures are available upon request (journalneurologyorg)

Copyright copy 2019 American Academy of Neurology Unauthorized reproduction of this article is prohibited