Movement Disorders - 2022 - Deuschl - European Academy of Neurology Movement Disorder Society European Section Guideline On

REVIEW
European Academy of Neurology/Movement Disorder Society-

European Section Guideline on the Treatment of Parkinson’s Disease:
I. Invasive Therapies
Günther Deuschl, MD, PhD,1* Angelo Antonini, MD, PhD,2 Joao Costa, MD, PhD,3 Katarzyna Śmiłowska, MD,1
Daniela Berg, MD, PhD,1 Jean-Christophe Corvol, MD, PhD,4 Giovanni Fabbrini, MD, PhD,5,6
Joaquim Ferreira, MD, PhD,7,8,9 Tom Foltynie, MD, PhD,10 Pablo Mir, MD, PhD,11,12,13
Annette Schrag, MD, PhD,14 Klaus Seppi, MD, PhD,15 Pille Taba, MD, PhD,16,17 Evzen Ruzicka, MD, PhD,18
Marianna Selikhova, MD, PhD,19 Nicholas Henschke, PhD,20 Gemma Villanueva, MSc,20 and Elena Moro, MD, PhD21
1
Department of Neurology, UKSH-Kiel Campus, Christian-Albrechts-University, Kiel, Germany
2
Parkinson and Movement Disorders Unit, Department of Neuroscience, University of Padua, Padua, Italy
3
Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
4
Institut du Cerveau-Paris Brain Institute, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Neurology, Centre
d’Investigation Clinique Neurosciences, Sorbonne Université, Paris, France
5
Department Human Neurosciences, Sapienza University of Rome, Rome, Italy
6
IRCCS Neuromed, Rome, Italy
7
Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
8
Instituto de Medicina Molecular João Lobo Antunes, Lisbon, Portugal
9
Campus Neurolo gico, Torres Vedras, Portugal
10
Department of Clinical & Movement Neurosciences, Institute of Neurology, London, UK
11
Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla Hospital
Universitario Virgen del Rocío/Universidad de Sevilla, Seville, Spain
12
Centro de Investigacio n Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain
13
Departamento de Medicina Facultad de Medicina, Universidad de Sevilla, Seville, Spain
14
Institute of Neurology, University Clinic London, London, UK
15
Klinik f. Neurologie, Medizinische Universität Innsbruck, Innsbruck, Austria
16
Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
17
Tartu University Hospital, Tartu, Estonia
-This
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- - - - - under
- - - - - the
- - - terms
- - - - - of- - the
- - - Creative
- - - - - - - - - - - - - - - - - - - - -Michael
- - - - - - J.- -Fox
- - - Foundation
- - - - - - - - - -(MJFF),
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- - - - -Black
- - - - -Charitable
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Commons Attribution-NonCommercial-NoDerivs License, which permits Cure Parkinson’s Trust, Innovate UK, Janet Owens Research Fellow-
use and distribution in any medium, provided the original work is prop- ship, Rosetrees Trust, Van Andel Research Institute, and Defeat MSA.
erly cited, the use is non-commercial and no modifications or adapta- He has served on advisory boards for Peptron, Voyager Therapeutics,
tions are made. Handl therapeutics, Living Cell Technologies, Bial, and Profile Pharma
and has received honoraria for talks sponsored by Bial, Profile
*Correspondence to: Prof. Dr. Günther Deuschl, Department of Pharma, and Boston Scientific. P. Mir has received grants from the
Neurology, UKSH, Kiel Campus, Christian-Albrechts-University, Arnold- Spanish Ministry of Science and Innovation, the Instituto de Salud
Heller-Straße 3, 24105 Kiel, Germany; E-mail: g.deuschl@neurologie. Carlos III-Fondo Europeo de Desarrollo Regional, the Consejería de
uni-kiel.de Economía, Innovacio n, Ciencia y Empleo de la Junta de Andalucía,
Relevant conflicts of interest/financial disclosures: G. Deuschl and the Consejería de Salud y Bienestar Social de la Junta de
reports a grant from Medtronic for the Earlystim study; minor fees from Andalucía and he has received honoraria for lecturing from Abbott,
Boston Scientific, Aleva, Functional Neuromodulation, and Roche for Allergan, Abbvie, Bial, Britannia, Italfarmaco, Merz, UCB, Roche,
review and DSMB activities; and minor royalties from Thieme Pub- Teva, and Zambon. A. Schrag has received grants from GE
lishers. A. Antonini reports a major grant from Abbvie. He has received Healthcare; consulted for Abbvie, Biogen, Roche, Neurotechnology,
honoraria for talks sponsored by Abbvie and has served on advisory Biogen, and Bial; and has received honoraria and royalties from
boards for Abbvie. D. Berg reports grants from Abbvie, Alexion Pharma, Oxford University Press. K. Seppi reports consultancies for Abbott,
Alnylam, Apopharma Inc., Biogen, BMWi, BMBF, Christa und Peter Stada, Grunenthal, AOP Orphan, Bial, Lundbeck, Roche, and Biogen
Thomsen Foundation, Coppenrath Foundation, Dapm Foundation, and grants from AOP Orphan, MJFF, and FWF Austrian Science Fund.
Desitin, EU, Else-Kröner-Fresenius Foundation, Gossweiler Foundation, He received payment for lectures from AOP Orphan, Abbvie, Stada,
Hoffmann La Roche AG, Icon Ltd + Biohaven Inc., Janssen Grunenthal, Ever Pharma, Licher Pharma, MDS, UCB, and Teva.
Pharmaceutica N.V., Jan von Appen Foundation, Lundbeck, Merck Ser- N. Henschke and G. Villanueva work for Cochrane Response, an evi-
ono, Parkinson Fonds Deutschland GmbH, Pfizer, Roche AG, Sanofi, dence services unit operated by Cochrane, and have no known con-
Sivantos GmbH, Stichting Parkinson Fonds, UCB, and Zambon. She flicts of interest. E. Moro reports consultancies for Abbott, Medtronic,
received payments for lectures from Abbvie, Bial, Biogen, Desitin, and Kyowa and major grants from Medtronic and Ipsen. She received
Movement Disorder Society (MDS), GE Healthcare, Feo GmbH, Nansen payment for lectures from Abbott and Medtronic. J. Costa, P. Taba,
Neuroscience Network, Parkinson bewegt e.V., UCB Pharma GmbH, E. Ruzicka, M. Selikhova, and G. Fabbrini declare no conflict of
and Zambon. J.-C. Corvol received honoraria for talks sponsored by interest.
Ever Pharma. J. Ferreira reports grants from Abbvie, Novartis, Received: 29 December 2021; Revised: 11 April 2022; Accepted: 22
Medtronic, and Fundação MSD. He received payment for lectures from April 2022
Bial, Abbvie, and Ipsen and has served on an advisory board for Bial.
He reports consultancies for Bial, Abbvie, Lundbeck, Biogen, Sunovion
Pharmaceuticals, and Affiris. T. Foltynie has received grants from the Published online 6 July 2022 in Wiley Online Library
National Institute of Health Research, Edmond J Safra Foundation, The (wileyonlinelibrary.com). DOI: 10.1002/mds.29066
1360 Movement Disorders, Vol. 37, No. 7, 2022

15318257, 2022, 7, Downloaded from https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29066 by Cochrane Mexico, Wiley Online Library on [10/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
T R E A T M E N T O F P A R K I N S O N ’ S D I S E A S E
18
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital
in Prague, Prague, Czechia
19
Southmead Hospital, Bristol Brain Centre, Bristol, UK BS10 5NB
20
Cochrane Response, London, UK
21
Division of Neurology, Grenoble, Grenoble Institute of Neurosciences, Grenoble Alpes University, Grenoble, France
A B S T R A C T : Background and Purpose: This update compared with current medical treatment. STN-DBS is the
of the treatment guidelines was commissioned by the best-studied intervention for advanced PD with fluctuations
European Academy of Neurology and the European not satisfactorily controlled with oral medications; it
section of the Movement Disorder Society. Although improves motor symptoms and QoL, and treatment should
these treatments are initiated usually in specialized cen- be offered to eligible patients. GPi-DBS can also be offered.
ters, the general neurologist should know the therapies For early PD with early fluctuations, STN-DBS is likely to
and their place in the treatment pathway. improve motor symptoms, and QoL and can be offered.
Methods: Grading of Recommendations Assessment, DBS should not be offered to people with early PD without
Development, and Evaluation (GRADE) methodology was fluctuations. LCIG and an apomorphine pump can be con-
used to assess the spectrum of approved interventions sidered for advanced PD with fluctuations not sufficiently
including deep brain stimulation (DBS) or brain lesioning managed with oral treatments. Unilateral MRgFUS of the
with different techniques (radiofrequency the- STN can be considered for distinctly unilateral PD within
rmocoagulation, radiosurgery, magnetic resonance registries. Clinical consensus was reached for the following
imaging–guided focused ultrasound surgery [MRgFUS] of statements: Radiosurgery with gamma radiation cannot be
the following targets: subthalamic nucleus [STN], ventrolat- recommended, unilateral radiofrequency thermocoagulation
eral thalamus, and pallidum internum [GPi]). Continuous of the pallidum for advanced PD with treatment-resistant
delivery of medication subcutaneously (apomorphine pump) fluctuations and unilateral radiofrequency the-
or through percutaneous ileostomy (intrajejunal levodopa/ rmocoagulation of the thalamus for resistant tremor can be
carbidopa pump [LCIG]) was also included. Changes in recommended if other options are not available, unilateral
motor features, health-related quality of life (QoL), adverse MRgFUS of the thalamus for medication-resistant tremor of
effects, and further outcome parameters were evaluated. PD can be considered only within registries, and unilateral
Recommendations were based on high-class evidence and MRgFUS of the pallidum is not recommended.
graded in three gradations. If only lower class evidence was Conclusions: Evidence for invasive therapies in PD is
available but the topic was felt to be of high importance, heterogeneous. Only some of these therapies have a
clinical consensus of the guideline task force was gathered. strong scientific basis. They differ in their profile of
Results: Two research questions have been answered with effects and have been tested only for specific patient
eight recommendations and five clinical consensus state- groups. © 2022 The Authors. Movement Disorders publi-
ments. Invasive therapies are reserved for specific patient shed by Wiley Periodicals LLC on behalf of International
groups and clinical situations mostly in the advanced stage Parkinson and Movement Disorder Society.
of Parkinson’s disease (PD). Interventions may be consid-
ered only for special patient profiles, which are mentioned Key Words: Parkinson’s disease; guideline; surgical
in the text. Therapy effects are reported as change interventions; infusion therapies
The first European guideline on the treatment of invasive therapies is the first. We have included inter-
Parkinson’s disease (PD) was published in 2006 con- ventions requiring surgery or invasive medication
sisting of two parts, the early uncomplicated disease1 delivery. Invasive treatments are usually considered
and late complicated disease,2 and were renewed in for advanced PD and cover deep brain stimulation
2013 as recommendations of European Federation of (DBS), pump therapies, and lesional therapies for the
Neurological Societies/Movement Disorder Society treatment of PD.
(MDS) for the diagnosis3 and management4 of Radiofrequency thermocoagulation of the thalamus
PD. The European Academy of Neurology (EAN) in and pallidus internus has a long history of treatment
collaboration with the European section of the MDS for PD. Initiated in the 1950s,6 it was practiced around
(MDS-ES) has now begun to produce regular updates the world in the following decades.7-10 These treat-
of the guidelines (GLs)5 according to GRADE method- ments were initially used because effective drugs to treat
ology. The GL task force has been set up from the two bradykinesia and tremor were not available yet. How-
societies to realize this task. The new PD GLs will be ever, when levodopa (L-dopa) became available in the
separated into several chapters of which this review on 1970s, lesional surgeries were largely abandoned with
Movement Disorders, Vol. 37, No. 7, 2022 1361

D E U S C H L E T A L
the exception of pallidotomy in some countries and Human fetal29,30 or stem cell transplantation or gene
thalamotomies for tremors unresponsive to oral treat- therapy31-33 are experimental treatments of PD and
ments, both on a small scale. However, the occurrence have currently no relevance for clinical care.
of L-dopa–induced fluctuations and dyskinesia triggered
the search for better interventions. As a result, lesional
pallidotomies were rediscovered, and subsequently DBS Scope
started its steep rise in the 1990s. Because of the general
Although there are individual GLs and evidence-
impression that DBS results in fewer complications,11
based medicine reviews on DBS and radiofrequency
which was confirmed by a randomized controlled trial
thermocoagulation lesions, the whole spectrum of inva-
in the year 2000,12 DBS has become the most fre-
sive interventions for PD has not been addressed in pre-
quently used intervention, and lesional procedures have
vious GLs. Furthermore, only the NICE-GL 2017,34
usually been reserved for specific situations.
which had a more limited focus, used GRADE-method-
DBS developed out of the aforementioned radi-
ology. The invasive interventions for PD share several
ofrequency thermocoagulation of the thalamus.13,14
features and merit a combined review: All are currently
Benabid and colleagues discovered that lesioning of the
mostly used for advanced stage PD except STN-DBS
thalamic ventralis intermedius (Vim) nucleus for tremor
and MRgFUS. They are all considered invasive proce-
can be replaced by electrical stimulation.15 After the dis-
dures as apomorphine infusion requires continuous
covery of the pathophysiologic role of the subthalamic
subcutaneous infusion, LCIG needs a percutaneous
nucleus (STN) by Bergman and colleagues,16 DBS elec-
jejunostomy, MRgFUS is an incisionless intracerebral
trodes were implanted in this nucleus17 to improve the
lesioning, and DBS and radiofrequency the-
broader symptom spectrum of PD. Radiofrequency the-
rmocoagulation require brain surgery through a burr
rmocoagulation pallidotomy18 was subsequently also
hole. Furthermore, all are more expensive than stan-
largely replaced by electrical stimulation of this nucleus.
dard drug treatments for PD. Health economics and
A large number of case series19 and finally randomized
cost-effectiveness of those interventions are beyond the
controlled studies have established the concept of DBS of
scope of these GLs, but existing systematic reviews are
the STN or the globus pallidus internus (GPi) for the
available.35
treatment of PD.20
Radiosurgery of the Vim with proton beams has also
been used since the late 1960s in few centers world- Methods
wide21,22 initially only for this nucleus. Although these
lesional procedures showed some benefits, few recent General
publications are available and are mostly case series, The methodology for the development of these GLs
and detailed reports of adverse effects or long-term con- has followed the framework provided by GRADE36
sequences are lacking. A very recent development is the and the recommendations of the EAN on the develop-
introduction of magnetic resonance imaging–guided ment of a neurological management GL.5 Population/
focused ultrasound surgery (MRgFUS). This is an inci- intervention/comparison/outcome (PICO) questions
sionless therapy that has mainly been assessed for were constructed according to GRADE standards and
essential tremor, and trials for PD are only beginning. are shown in the Appendix S1 Methods section (see
This technique is currently used within the thalamus Table App1.1a and b). References used in the current
but lesioning of the STN was also recently reported.23 GLs were identified by performing a systematic search
Among pharmacological interventions, the concept of in the PubMed, Embase, Web of Science, and Cochrane
reducing dopaminergic hypersensitivity and maintaining Library databases as well as clinical trials registration
constant plasma levels by continuous stimulation of via clinicaltrials.gov in accordance with the Preferred
dopaminergic terminals has emerged,24 resulting in the Reporting Items for Systematic Reviews and Meta-
treatments of continuous subcutaneous infusion of Analyses statement.37 The literature search for each
apomorphine25 or intrajejunal application of L-dopa– PICO was conducted from the earliest possible date to
carbidopa intestinal gel (LCIG) preparations.26 Apo- December 31, 2020. Two people (from either EAN [K.
morphine hydrochloride (apomorphine) has been S., G.D., E.M., A.A.] or Cochrane Response [G.V.,
proposed for the treatment of PD since the 1950s,27 N.H.]) independently screened all citations and
but it had been used only in a few movement disorder abstracts identified by the search. Articles were selected
centers since then.25,28 During the past decade, it has based on the following eligibility criteria: (1) original
been used more widely, in parallel with the technologi- research and/or (2) randomized clinical trial (RCT)
cal advances of infusion pump devices. Apomorphine and/or (3) metanalysis/systematic review and (4) per-
can also be administered using intermittent subcutane- formed in people with PD. Data were extracted in Dis-
ous pen injection for individual off periods, which is tillerSR and summarized in GRADE evidence profiles.
not discussed here. The writing group (G.D., A.A., J.C., K.S., E.M.) of the

GLs shared the tasks of the systematic review and TABLE 1 Narrative wording of the combined evaluation of the
developed the first draft of the GLs. Every member of outcomes depending on effect size and certainty according to Grading of
the GL group voted on each of the recommendations. Recommendations Assessment, Development, and Evaluation38
Members with a possible conflict of interest for specific High certainty of evidence
questions abstained from voting. Cochrane Response, a
fee-for-service organization of Cochrane, was assisting Large effect Intervention results in a large reduction/
the GL task force to produce these GLs. increase in outcome
For further details regarding search strategy, study Moderate Intervention results in reduction/increase
selection, data extraction, assessment of risk of bias, in outcome
data synthesis, summarizing and interpreting results, Small, important Intervention results in a slight reduction/
see the Appendix S1 Methods section. increase in outcome
Small, unimportant Intervention results in no reduction/
Outcomes increase in outcome
These GLs considered the following three main Moderate certainty of evidence
aspects important for clinical decision-making:
Large effect Intervention likely results in a large
1. Objective outcomes are usually graded by the clini- reduction/increase in outcome
cian with clinical scales and include measures of
Moderate Intervention probably results in a
mobility as well as nonmotor outcomes if they are
reduction/increase in outcome
not patient reported (eg, instrumented measures of
mobility, sleep). A typical example is the Unified Small, important Intervention probably results in a slight
Parkinson’s Disease Rating Scale Part III reduction/increase in outcome
(UPDRS-III). Small, unimportant Intervention likely results in little to no
2. Measures of function and/or well-being of the difference in outcome
patient. The majority of reported outcomes are Low certainty of evidence
based on patient-reported outcome measures such as
health-related quality of life (QoL; eg, 39-Item Large effect Intervention may result in a large
Parkinson’s Disease Questionnaire [PDQ-39]) or are reduction/increase in outcome
completed by the clinician based on an interview Moderate Intervention may reduce/increase
with the patient (eg, Schwab and England scale, Uni- outcome
fied Parkinson’s Disease Rating Scale Part II
Small, important Intervention may reduce/increase
[UPDRS-II]). outcome slightly
3. Adverse events (AEs) are to be balanced against the
benefit. AEs are defined as any undesirable experi- Small, unimportant Intervention may result in little to no
ence associated with the use of a medical (or a difference in outcome
device) product in a patient and can cover all aspects Very low certainty of the evidence
of health. AEs are standardized into serious AEs
(SAEs) and AEs. Death, life-treating conditions, hos- Any effect The evidence is very uncertain about the effect
of intervention on outcome
pitalization and prolonged hospitalization, disability,
and permanent damage are considered SAEs. For
surgical studies, surgical SAEs are considered
separately. Appendices S3 and S4). The MCIC was derived from
previous studies and was the subject of a consensus
‘Critical’ and ‘important’ outcomes were defined in the within the GL group. Whenever anchor-based MCIC
PICOs (see Appendix S1, Table App 1. 1a,b). The criti- were not available, Cohens’ d as a distribution-based
cal outcomes were considered more relevant for deci- statistical measures was used as the only benchmark.
sion making than the “important” outcomes. The data Details see Appendix S5 with the explaining appendices
were analyzed as short-term effects (≤12 months) and S3 and S4.
medium-term effects (>12 months). For each critical
and important outcome, the pooled estimates of effect
are presented with 95% confidence intervals with the Wording of Recommendations
anchor-based minimal clinically important change The wording of the recommendations is based on the
(MCIC) for each outcome (Appendix S1, Table 2), the current standards for GRADE GLs.38 This terminology
effect size as expressed by Cohen’s d, the number of is evaluating first the degree of certainty of the recom-
studies and participants, and the GRADE rating for the mendation (bias, imprecision, etc.) and, second, the
certainty of evidence (see Appendix S5 with explaining strength of the recommendation. For rating the

strength, we used the MCIC as defined previously and medical treatment (BMT), two studies on STN-DBS
the effect size, according to Cohen’s d, to determine if versus GPi-DBS, one study on apomorphine, and two
the effect was small, moderate, or large in the following studies on LCIG.
way: If an accepted MCIC threshold is available for a For lesional therapies, 1297 articles were screened
specific outcome parameter and the point estimate for (see Appendix S2, Fig. App2.2), and three studies were
the outcome is below the MCIC threshold, the effect is included (two on radiofrequency thermocoagulation of
considered the pallidum and one on MRgFUS therapy). For more
details, see the Search and Search Results section in
• Trivial, small unimportant effect or no effect, if the Appendix S2.
point estimate is not significant.
• Small effect, if the point estimate is significant and if
the GL group considered the effect relevant despite Interventions, Targeted Brain Structures, and
being below the MCIC threshold. Patient Profiles Discussed in These GLs
If an MCIC threshold is available for a specific outcome The studies were to be separated by the following
parameter and the point estimate for the outcome is intervention types: DBS with implantation of an elec-
above the MCIC threshold, the effect size of the effect trode that reversibly modulates brain circuits, radi-
can be a small important, moderate, or large effect, ofrequency thermocoagulation producing thermal
depending on the result for the Cohen’s d: localized lesions. Both procedures require brain sur-
gery through a burr hole for each brain side. Radio-
• Small effect if the difference is significant and surgery is producing brain lesions with stereotactic
Cohen’s d is 0.2 to 0.35. radiation through the intact scalp. MRgFUS is pro-
• Moderate effect if Cohen’s d is >0.35 and <0.65. ducing lesions with high-energetic focused ultrasound.
• Large effect if the effect is significant and Cohen’s Both procedures are incisionless. Apomorphine pump
d is >0.65. treatment is applied through subcutaneous continuous
infusion, and LCIG requiring a permanent percutane-
If an MCIC threshold is not available for a specific
ous jejunostomy for infusion of L-dopa into the duo-
outcome parameter, the size of the effect can be:
denum. The studies were also separated for the
• Trivial, small unimportant effect or no effect if the targeted nucleus in the brain (STN, GPi, and Vim).
difference is not significant. For early PD with early fluctuations and for early PD
• Small effect if the difference is significant and without fluctuations, studies have considered only the
Cohen’s d is <0.35. STN as the DBS target. For advanced PD, four of the
• Moderate effect if the difference is significant and six studies included only STN-DBS patients, whereas
Cohens d is >0.35 and <0.65. two studies had patients with mixed targets: one with
• Large effect if the difference is significant and 51/121 GPi, 60/121 STN, and 134 BMT40 and the
Cohen’s d is >0.65. other with 4/178 GPI, 174/178 STN, and 183 BMT.41
The benefits and risks of STN-DBS versus GPi-DBS
The wording of the summary of findings is based on are presented in a separate paragraph as there are two
the most recent GRADE recommendation38 and shown large RCTs comparing the effects between the two
in Table 1. targets.42,43 Mostly uncontrolled trials with radi-
All recommendations were graded by the GL group ofrequency thermocoagulation have been published
in light of clinical circumstances. For some of the PICO for Vim, GPi, and STN. MRgFUS and radiosurgery
questions/interventions, no RCTs could be found, and trials are available for Vim and STN. Finally, the dif-
grading of the evidence was therefore impossible. For ferent RCTs have recruited different patient groups.
each of these interventions, the GL group has worded a Most invasive interventions were tested for patients
clinical consensus statement according to EAN with advanced PD with fluctuations and dyskinesia that
standards.39 can no longer be satisfactorily treated with oral medica-
A detailed protocol of the GL development can be tion. This also includes treatment-resistant tremor.44
found in the full GLs (see the online attachment). The group is labeled here as advanced PD. Patients
with motor fluctuations since <3 years after onset can
Results and Recommendations usually still be treated with medication but were specifi-
cally tested in RCTs and are labeled as early PD with
Search Results early fluctuations. An additional patient group are those
In total, the database search yielded 2600 articles on who are not yet fluctuating and still have a favorable
nonlesional therapies (see Appendix S2, Fig. App2.1). response to drugs even if extended medication regimens
Based on the aforementioned criteria, 13 studies were are needed. They are called early PD without fluctua-
included. Specifically, eight studies on DBS versus best tions. Two additional specific patient groups are those

FIG. 1. Recommendations for invasive therapies tested in different patient groups with randomized controlled studies (for details of the recommenda-
tions, see the text). To facilitate the reader’s overview, we present them along with this guideline’s abbreviated recommendations for the various inter-
ventions. DBS, deep brain stimulation; Gpi, pallidum internum; L-dopa, levodopa; PD, Parkinson’s disease; STN, subthalamic nucleus; Vim, ventralis
intermedius; MRg, Magnetic resonance imaging guided.
with treatment-resistant tremor and those with predom- Summary of Findings

inant unilateral symptoms. These RCTs show that STN-DBS probably results in
Figure 1 gives an overview of the different aspects of a large improvement of QoL, a large improvement of
these GL recommendations. activities of daily living (ADLs), and a large improve-
ment of motor impairment in these patients. There is
Evidence, Summary of Findings, and likely to be a large effect on motor fluctuations and dys-
Recommendations kinesia, the typical complications of long-term medical
Presentation of the data is separated for non- therapy, particularly with a moderate increase in daily
lesional and lesional therapies. The effects of the ON time and a moderate reduction in daily OFF time.
interventions are discussed in the next sections and Hoehn and Yahr stage may be slightly improved. Cog-
shown in an abbreviated form in Figure 2 and nition and depression as important outcomes are likely
detailed in Appendix S3 (Effects of Intervention sec- neither improved nor worsened.
tion), Appendix S4 (Forest Plots section), and Appen- SAEs are more common for the surgically treated
dix S5 (Summary of Findings section). They are also patient group than for those on BMT. A total of
partly repeated in the next paragraphs. The wording 152 SAEs are described in 604 patients (25%) in the
of the results follows the suggestions of GRADE (see DBS group versus 52 SAEs/469 patients (11%) in the
Table 1).38 All comparisons of effects and adverse BMT group. Most surgery-related AEs were reversible.
effects are against standard noninvasive treatments Patients seeking DBS have more suicidal ideation and
(medication). suicides than the general population,48,49 but rates in
the treated group do not differ from the comparator
group on BMT,49 suggesting that this is not an effect of
Nonlesional Therapies the treatment.
STN-DBS for Advanced PD with Medically
Unresponsive Fluctuations or Medically Considerations of the GL Task Force
Unresponsive Tremor Eligibility criteria are important for the selection of
The most extensively studied intervention is STN- patients for this treatment. The most important preop-
DBS for advanced PD, with six RCTs against best erative predictor of outcome is response to L-dopa dur-
medical treatment BMT,40,41,45-47 of which one had a ing a formal L-dopa test.50 Most studies reported a
double-blind design.47 A study on DBS for the GPi minimum of 33% improvement as an inclusion crite-
against medical treatment was not identified, but two rion, and lower values have shown poorer treatment
studies compared stimulation of the STN and results.51 Tremor as a symptom is responding particu-
GPi.42,43 larly well to STN-DBS, even if not well responding

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Movement Disorders, Vol. 37, No. 7, 2022

FIG. 2. Overview of clinically meaningful outcomes of invasive therapies for PD. The results are shown for all the interventions that have high-class clinical studies. The outcomes are classified
according to effect size and certainty of the effects based on Grading of Recommendations Assessment, Development, and Evaluation criteria. The results are separated into the different levels of rec-
ommendation. DBS, deep brain stimulation; Gpi, pallidum internum; L-dopa, levodopa; MRgFUS, magnetic resonance imaging–guided focused ultrasound surgery; PD, Parkinson’s disease; RF, radi-
ofrequency; SAE, serious adverse event; STN, subthalamic nucleus; UPDRS-II, Unified Parkinson’s Disease Rating Scale Part II; UPDRS-III, Unified Parkinson’s Disease Rating Scale Part III; UPDRS-
IV, Unified Parkinson’s Disease Rating Scale Part IV; Vim, ventralis intermedius.
during the L-dopa test.52 Age may also be a predictor of improvement of motor symptoms. The evidence is very
response, but this has not yet been convincingly demon- uncertain about the effect on complications of therapy.
strated because some studies have found no effect of Daily ON time without dyskinesia and OFF time may
age53 but others have, and most studies had an age be improved. STN-DBS may result in no difference
limit at 70 years. There are also neurosurgical contrain- regarding cognition and apathy. STN-DBS may
dications (eg, severe brain atrophy), uncontrolled improve depression. The effect sizes are similar to
depression, psychosis, or dementia. The expert group advanced PD. DBS may improve impulsive–compulsive
suggests consideration of overall health and biological behaviors in the long term. STN-DBS probably
age rather than the numerical age. improves gait62 and reduces the daily dosage of medica-
Several uncontrolled retrospective and prospective tion.61 STN-DBS may increase the likelihood of
studies report on the value of STN-DBS for the treat- experiencing SAEs. They occurred in 54.8% of the
ment of several nonmotor symptoms of the disease. patients in the neurostimulation group and in 44.1% of
This includes a reduction of mood fluctuations, halluci- those in the best medical treatment group. In the DBS
nations, and psychosis and improvements in urinary group, 13.7% experienced gait impairment as an AE in
incontinence and sleep.52,54-56 An open 3-year study in contrast to 11.8% in BMT group. Long-term data are
67 STN-DBS patients matched with 84 medically not yet published for this cohort.
treated patients showed significant differences on the
nonmotor symptom scale, particularly for sleep, fatigue, Considerations of the GL Task Force
and urinary symptoms.55
Inclusion criteria are important: Patients in this group
Long-term outcome of STN-DBS cannot be assessed
were aged younger than 61 years at surgery, the
in randomized controlled studies. However, a number
improvement at the preoperative L-dopa test was 50%
of uncontrolled long-term studies of patients with
or higher, and there were no cognitive changes or
advanced PD and STN stimulation are available and
uncontrolled psychiatric conditions. A secondary analy-
underwent multiple meta-analyses.52,57,58 These reveal
sis showed that the effect on QoL depends on the base-
that STN-DBS is still effective beyond 15 years after the
line PDQ-39 score, with those having a worse PDQ-39
intervention, with significant improvement in motor
baseline score having better postoperative improve-
complications and a stable reduction of dopaminergic
ment.63 Thus, a subjectively relevant affection of QoL
drugs.59 Certainly, these cohorts are highly selected and
might be a further inclusion criterion.
most do not report the disease course of patients lost at
The GL group concludes that STN-DBS can be
follow-up. Maintenance of QoL above the preoperative
offered to people with early PD and early fluctuations
level has been found for 5 years after surgery despite
who fulfil the inclusion and exclusion criteria for DBS.
the natural progression of the disease.58,59
Less is known about the long-term course of these
The GL group concludes that STN-DBS should be
patients than for patients with advanced disease.
offered to eligible patients with PD with medically resis-
tant fluctuations. Stringent inclusion and exclusion
Recommendation 2: Consider offering STN-DBS to
criteria need to be applied at specialized centers for
people with early PD and early fluctuations
each patient.
(15 voters, 100%).
Recommendation 1: Offer STN-DBS to people with
advanced PD if fluctuations are not satisfactorily
controlled with medication or if tremor cannot be STN-DBS for People with Early PD Without
controlled with medication (15 voters, 100%). Fluctuations
The study published by Charles and colleagues64,65 is
the only study on implantation of STN-DBS at a stage
where fluctuations have not yet occurred. Inclusion
STN-DBS for Early PD with Early Fluctuations
criteria were the following: Hoehn and Yahr stage II in
Two studies were included in the review.60,61 Overall, the off state, antiparkinsonian medications for more
271 patients with PD aged younger than 60 years and than 6 months but less than 4 years, and no current or
with fluctuations or dyskinesia for less than 3 years prior history of motor fluctuations. A total of
were randomly assigned to STN-DBS or BMT. 30 patients were randomly assigned, and outcomes
were reported for 12 and 24 months of follow-up.
Summary of Findings
STN-DBS in early PD with early fluctuation com- Summary of Findings
pared with BMT results in a large improvement of The critical outcomes PDQ-39, ADLs (UPDRS-II),
QoL, a large improvement of ADLs, and a large motor score while OFF (UPDRS-III), and disease

complications (Unified Parkinson’s Disease Rating Scale dopaminergic medication compared with STN-DBS both
Part IV [UPDRS-IV]) were not different between the in the first year of follow-up and during a longer term
DBS and BMT groups. Similarly, medication change follow-up.
from baseline to 24 months was not significantly differ-
ent between the DBS and BMT groups despite substan- Considerations of the GL Task Force
tially increased dosages. Two serious AEs occurred in
The 3-year, open-label, follow-up data of the VA
the DBS group.
study53 showed a stable result of the critical outcome
parameters, whereas the 3-year follow-up of the
Considerations of the GL Task Force Netherlands study67 concluded that motor symptoms
The study has limitations as the sample size was small and functioning during the off-drug phase were more
(15 people with PD per arm). According to the inclu- improved after STN-DBS than after GPi-DBS, with no
sion criteria, patients eligible for the study did not expe- differences for cognition, mood, or behavior.
rience motor fluctuations; however, the difference The studies show only minor differences between
between the UPDRS-III in the OFF and the ON states STN-DBS and GPi-DBS during the 3-year observation
was 43% at baseline, suggesting that the patients were period. Although these differences may be important
already fluctuating. At 24 months of follow-up, the for particular patients, they do not allow prioritizing
UPDRS-III score in the ON state did not differ from the one treatment over the other. Therefore, both targets
baseline score, and there was worsening of the UPDRS- are similarly effective to treat symptoms of advanced
III score off medication compared with baseline. The PD and can both be recommended. The greater reduc-
authors stated that a neuroprotective effect can be seen tion of L-dopa for those treated with STN-DBS was
in DBS group; however, no current evidence supports considered an important clinical difference.
this view. Further studies are underway.
The GL group concludes that STN-DBS should not Recommendation 4: Both STN-DBS and GPi-DBS
be offered to people with PD without fluctuations. are effective to treat symptoms of advanced PD with
fluctuations, but dopaminergic medication can be
Recommendation 3: Do not offer DBS to people with more reduced with STN-DBS (16 voters, 100%).
early PD without fluctuations (16 voters, 100%).
LCIG for Advanced PD

STN-DBS versus GPi-DBS in PD
Two studies are identified on the LCIG treatment of
The majority of RCTs for DBS in PD have investi-
advanced PD: one 3-month, double-blind, double-
gated STN-DBS. Nevertheless, in some countries, dummy study68 of LCIG versus oral immediate release
GPi-DBS is commonly used. There are only two RCT L-dopa plus in patients with otherwise stable anti-
studies comparing GPi-DBS versus STN-DBS. The
parkinsonian treatment and a second study against
American Veterans Administration (VA) study43 ran- optimized oral treatment (Results of one of the studies
domly assigned 152 patients to GPi-DBS and 147 to (DYSCOVER) published only on www.
STN-DBS. The Netherlands study randomly assigned
clinicaltrials.gov).
62 patients to GPi-DBS and 63 patients to STN-
DBS.42 Duration of the studies was 24 months43 and
12 months,42 respectively. Summary of Findings
QoL assessed by the PDQ-39 and PDQ-8 probably
results in a large improvement compared with oral
Summary of Findings treatment. Similarly, LCIG probably resulted in large
The analysis of both studies shows that most critical improvement of ADLs. ON time with troublesome dys-
and important outcomes were not different. This applies kinesia was probably moderately improved in the over-
for QoL (PDQ-39), ADLs (UPDRS-II) at 1 and 2 years, all group. There was moderate decrease in daily OFF
motor score (UPDRS-III in the off medication state) at time in the LCIG group compared with oral treatment.
1 and 2 years, complications of therapy, ON time with- LCIG application may result in little or no difference in
out troublesome dyskinesia, SAEs, Hoehn and Yahr daily dosage of anti-PD medication compared with best
staging, and cognition.53,66 A minor improvement of medical treatment.
depression in the GPi group was found in the US AEs were very common (>95% of the patients).
study.43 There was a greater reduction in L-dopa dosage Three patients discontinued treatment: one because of
in the STN groups of both studies. GPi-DBS was associ- psychosis, one because of peritonitis/pneumonia, and
ated with a greater increase of daily dose of one had postprocedural discharge. No patients died.

Most of the SAEs/AEs were related to the gastro- apomorphine group. Apomorphine infusion probably
jejunostomy, and as both treatment groups had this results in a decrease in the daily dosage of anti-PD medi-
intervention, there is no difference between the two cation in the short term.
groups. A total of 63 patients (89%) had device-related
complications, including tube dislocations, percutane- Considerations of the GL Task Force
ous gastrojejunostomy, insertion complications, stoma Multiple open-label studies confirmed the efficacy of
insertion complications, pump malfunctions, and apomorphine in the reduction of daily off time. In addi-
pneumoperitoneum. The AEs occurred mostly within tion, some the studies reported a reduction of dyskine-
the first week and resolved in all cases, but the observa- sia severity; however, these data from open-label trials
tion period was only 3 months. have to be interpreted accordingly. Some GL members
consider apomorphine infusion the least invasive of the
Considerations of the GL Task Force treatments discussed here.72
Given the fact that the controlled study duration was
only 3 months, limited evidence is available on long- Recommendation 6: Consider offering apomorphine
term benefits and complications. Open-label, longer pump infusion for people with advanced PD if fluc-
term (2 years) changes in UPDRS-IV items for OFF tuations are not satisfactorily controlled with medi-
time and ON time have been assessed with a multina- cation (15 voters, 100%).
tional national prospective registry. This registry also
included assessments of nonmotor symptoms and QoL,
showing continued improvement compared with base-
line.69 SAEs have not only been reported in the con- Lesional Neurosurgical Therapies
trolled study but also in open-label studies, including
even life-threatening complications.69,70 Historically, the first invasive treatment for the treat-
The GL group concluded that the treatment can be ment of advanced PD was radiofrequency the-
considered for people with advanced PD and disabling rmocoagulation brain surgery, dating back to the
fluctuations but knowledge about the treatment results 1950s.13 In the 1990s, localized lesions with radiation
beyond 3 months is limited. Its value for dyskinesia has were proposed.22,73 However, radiofrequency the-
not yet been established. rmocoagulation lesions have been progressively aban-
doned because of better results with DBS or the
Recommendation 5: Consider offering LCIG for peo- unavailability of these procedures in many coun-
ple with advanced PD if fluctuations are not satisfac- tries.74,75 The latest and most advanced lesional but
torily controlled with medication (15 voters, 100%). incisionless intervention is MRgFUS with few
RCTs74,75 and several uncontrolled studies published in
the past 10 years. As outlined previously, the brain tar-
gets for lesional procedures are similar for all available
Apomorphine Infusion for interventions. Clinical trials for different interventions
Advanced PD and targets are evaluated separately in this GL.
One recent RCT with a 12-week double-blind phase Radiofrequency Thermocoagulation

and a 52-week open-label phase71 was identified.
Patients received either continuously infused subcutane- Pallidotomy with Radiofrequency
ous apomorphine or placebo. Concomitant medication Thermocoagulation
was reduced when dopaminergic adverse effects (eg, The success of Leksells’ pallidotomy18 was one of the
dyskinesia) occurred during the hospital stay of reasons for the revival of unilateral pallidotomy, partic-
<10 days at the beginning of the treatment phase. Res- ularly in North America at the turn of the century.76
cue doses up to 300 mg oral L-dopa were allowed. However, the evidence for this treatment is weak.
Two unblinded RCTs with 36 and 37 patients were
Summary of Findings included77,78 and compared outcomes for the pallidotomy
Apomorphine showed no relevant effect on QoL or group with a medical therapy group. QoL was reported in
the motor score in the ON condition. There was a mod- one study, and pallidotomy may improve QoL (PDQL).
erate improvement in daily on time without troublesome The intervention may slightly improve ADLs (UPDRS-II)
dyskinesia in the apomorphine group compared with and the motor score (UPDRS-III). Pallidotomy probably
BMT. Similarly, there was a moderate improvement in reduces complications of therapy (UPDRS-IV). SAEs were
daily off time in the apomorphine group compared with more common in the pallidotomy group. Pallidotomy
BMT. AEs and SAEs were more common in the may make little or no difference to the Hoehn and Yahr

score. The evidence is uncertain if pallidotomy improves tested in an RCT.87 It cannot be recommended by this
depression and gait. Long-term data of these trials have GL group as a treatment for advanced PD.
not been published, but case series on pallidotomies have Clinical Consensus Statement 2: RCTs for unilateral
reported positive long-term data for up to 5 years.76,79-81 radiofrequency thermocoagulation of the STN for peo-
The GL committee concluded that unilateral pallidotomy ple with PD are not available. Due to potential high
can be considered as a treatment option for advanced PD risks for Aes, this GL task force does not recommend
with medically intractable treatment complications in the this treatment (16 voters, 100%).
absence of other more efficacious and better established
treatment options for the particular patient, but the rec-
ommendation is considered very weak.
Radiosurgery with Gamma Radiation
Recommendation 7: Consider offering unilateral pal-
lidotomy with radiofrequency thermocoagulation to Treatment with radiosurgery is available in only few
people with advanced PD who experience trouble- centers worldwide, and no RCT has been published
some fluctuations and for which DBS or pump ther- with this method for the treatment of advanced PD or
apies is not a treatment option (16 voters, 100%). tremor of PD. Open-label and prospective collections of
case series are available. One study used blinded evalu-
ation outcomes.88 The occurrence of potentially danger-
ous adverse effects such as continuing evolving lesions
Thalamotomy with Radiofrequency long after the application of the radiation were
Thermocoagulation reported.89 In contrast to all other interventions, there
is no possibility to control the effect of the lesion before
This procedure has been used to treat thousands of it is complete because the destruction of the tissue and
people with tremor-dominant PD and has mostly been subsequent clinical effects due to radiation take days to
applied unilaterally. Bilateral application had the disad- weeks. Therefore, a reversible test is not possible. We
vantage of frequent dysarthria in up to 40% of the are aware that it is an incisionless procedure that may
patients,82 and it has, therefore, only been applied since be needed for rare clinical situations, but other inter-
the second half of the last century. The higher number ventions are available and should be preferred.
of AEs with radiofrequency compared with thalamic These facts have led this GL group not to consider it
DBS for unilateral and particularly for bilateral proce- as a treatment option. It is not a recommended option
dures was shown in a controlled trial12,83 and was the for the treatment of advanced PD, neither as
main reason that this treatment has mostly been aban- thalamotomy, pallidotomy, nor as a lesioning technique
doned. This GL group identified no RCTs that fulfill for the STN.
the inclusion criteria, and no recommendations Clinical Consensus Statement 3: RCTs for unilateral
according to the GRADE-methodology are possible. gamma radiation radiosurgery of any of the three target
Therefore, the procedure cannot be recommended. nuclei are not available for people with PD. Due to
However, the GL committee is aware that unilateral potential high risks for Aes, this GL task force does not
procedures are still used for selected indications (eg, recommend this treatment (16 voters, 100%).
patients with repeated infected DBS electrodes) when
no other treatment options are available or in countries
that have no other interventions available.
Clinical Consensus Statement 1: RCTs for unilateral Magnetic Resonance Imaging–
radiofrequency thermocoagulation of the thalamus for
parkinsonian tremor or advanced PD are not available,
Guided Focused Ultrasound
and formal recommendations are not possible. As DBS Lesioning
has a better safety profile, this GL task force does not
Unilateral Thalamotomy with MRgFUS
recommend this treatment if safer treatments are avail-
able (16 voters, 100%). One MRgFUS system is approved in Europe
(CE mark for essential tremor, PD tremor, and neuro-
pathic pain since 2012)90 and in the United States for
Lesioning of the STN with Radiofrequency treating essential tremor (since 2016).91 Its use in par-
Thermocoagulation kinsonian tremor is based on a study with 20 patients
There is only one larger case series on radiofrequency receiving active treatment and seven receiving sham
lesioning of the STN, which concluded acceptable feasi- treatment.75 As the latter number is below the threshold
bility84,85 with an open follow-up.86 It reported some required for this GL, the study was excluded. There are
efficacy but also some cases with ongoing surgically several additional case series in people with PD with
induced dyskinesia. The procedure has never been tremor.92,93

Although promising, this GL does currently not rec- applied unilaterally in a highly selected group of people
ommend the treatment because of the lack of appropri- with unilaterally dominant PD. Therefore, preliminary
ate data. Further studies are needed. data suggesting that MRgFUS may be cost-effective com-
Clinical Consensus Statement 4: No sufficient RCTs pared with DBS should be interpreted with caution.96
available for uni- or bilateral MRgFUS of the thalamus The majority of people with advanced PD have bilateral
for medically resistant tremor in PD. Despite promising disease, but it is unknown whether MRgFUS sub-
preliminary data, this treatment should only be applied thalamotomy can be safely and efficiently performed
within clinical studies or registries (16 voters, 100%). bilaterally.
Despite initial promising results, currently the treat-
Unilateral Pallidotomy with MRgFUS ment cannot be recommended outside clinical studies.
Only one small case series has been published so
far.94 These GLs do not recommend the treatment Recommendation 8: Consider using unilateral
because appropriate data are lacking. MRgFUS of the STN in people with distinctly unilat-
Clinical Consensus Statement 5: Do not use MRgFUS eral PD only within clinical studies or registries due
of the pallidum for advanced PD with fluctuations out- to the limited data on this new treatment
side clinical studies (16 voters, 100%). (16 voters, 100%).
Unilateral Lesioning of the STN with MRgFUS

(MRgFUS subthalamotomy) Future Developments
In a controlled trial,95 27 patients were randomly
assigned to unilateral subthalamotomy and 13 to sham These GLs is the first to evaluate all currently avail-
treatment. The patients were relatively young able invasive treatments for PD and is part of a series
(57.1 9.1 years) and had a relatively short disease that will cover all the other treatment options and
duration (6.2 3.0 years) and pronounced unilateral essential diagnostic procedures for PD. There is only
disease. limited evidence for several of the invasive treatments
for PD. Using the rigorous GRADE methodology, the
Summary of Findings GLs only consider RCTs for evaluation but describe the
spectrum of approved interventions. Economic evalua-
Focused ultrasound subthalamotomy may improve
tions of the treatment options are not yet included and
QoL (PDQ-39), probably improves ADLs (UPDRS-II),
will likely differ between regions with different health
and probably improves the motor score (UPDRS-III). It
care systems and the large variation in the availability
may also reduce complications of therapy (UPDRS-IV).
and costs of these treatments. However, the EAN is
No information was available for the following out-
working on including this in the future. A number of
comes: the total UPDRS, cognition, depression, apathy,
careful studies are available that compare the costs for
impulsive–compulsive behaviors, gait, and speech.
the different treatments for specific countries.35,96-101
Focused ultrasound may result in a decrease in daily
Several invasive interventions for PD have undergone
dosage of anti-PD medication in the short term.
a rapid development, with DBS of the STN and GPi
Short-term AEs were more common in the sub-
being established treatments for the improvement of
thalamotomy group, including dyskinesia in the off
motor symptoms and health-related QoL.20 Further
medication state, weakness of the treated body side,
questions on the use of DBS for psychosocial impact
facial asymmetry, speech disturbance, gait disequilib-
and nonmotor symptoms in PD as well as the possible
rium, somnolence, and binge eating. At 12 months, one
usefulness for axial abnormalities still need to be
patient still had speech disturbance and one patient had
answered. Limited research activity is available for
unsteadiness. Intraprocedural AEs were headache and
radiosurgery for PD.102 No randomized controlled
dizziness that resolved after 1 day. There were neither
studies on lesional procedures with radiofrequency the-
intracerebral hemorrhages nor infections. So far only
rmocoagulation have been published, and this treat-
1-year data are available.
ment may remain a last resort treatment for special
cases in the hands of experienced specialized functional
Considerations of the GL Task Force neurosurgeons. Research and use of MRgFUS is cur-
This treatment is new, and only one RCT is available. rently rapidly developing, but important questions are
The results are promising regarding the standard out- still open.23 One conceivable indication for this inter-
comes for advanced PD. The AEs are frequent, but lon- vention is treatment-resistant parkinsonian tremor, but
ger term sequela are mild and rare. Many key questions, the first focused ultrasound thalamotomy trial failed
however, remain open regarding this treatment: Long- the threshold of this GL because the study was under-
term data beyond 1 year are lacking. The treatment was powered. Infusion therapies are another active field of

research, and other new forms of less-invasive interven- 12. Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of
continuous thalamic stimulation and thalamotomy for suppression
tions are currently being developed. New trials may of severe tremor. N Engl J Med 2000;342(7):461–468.
also explore the treatment of other, particularly non- 13. Spiegel EA, Wycis HT, Marks M, Lee AJ. Stereotaxic apparatus
motor, symptoms of PD. for operations on the human brain. Science 1947;106(2754):
The invasive treatments discussed should only be 349–350.
used for appropriately selected patients, but in those 14. Hassler R, Mundinger F, Riechert T. Stereotaxis in Parkinson Syn-
drome: Clinical-Anatomical Contributions to its Physiology, with
can profoundly change the lives of people with PD. an Atlas of the Basal Ganglia in Parkinsonism. Berlin, Heidelberg,
New York: Springer Verlag; 1979.
15. Benabid AL, Pollak P, Hommel M, Gaio JM, de Rougemont J,
Acknowledgments: Cochrane Response was contracted by European Perret J. Treatment of Parkinson tremor by chronic stimulation of
Academy of Neurology/Movement Disorder Society, European
the ventral intermediate nucleus of the thalamus. Rev Neurol
Section (EAN/MDS-ES) to conduct the systematic review. The GL devel-
opment was further supported by travel grants for meetings and support (Paris) 1989;145(4):320–323.
for online meetings by EAN/MDS-ES. GL team members were not paid. 16. Bergman H, Wichmann T, DeLong MR. Reversal of experimental
Katarzyna Śmiłowska was supported with a stipend of the Medical Fac- parkinsonism by lesions of the subthalamic nucleus. Science 1990;
ulty of the Christian-Albrechts-University, Kiel. Open Access funding 249(4975):1436–1438.
enabled and organized by Projekt DEAL.
17. Pollak P, Benabid AL, Gross C, et al. Effects of the stimulation of
the subthalamic nucleus in Parkinson disease. Rev Neurol 1993;
149(3):175–176.
18. Svennilson E, Torvik A, Lowe R, Leksell L. Treatment of parkin-
Data Availability Statement sonism by stereotatic thermolesions in the pallidal region. A clinical
The data that support the findings of this study are evaluation of 81 cases. Acta Psychiatr Scand 1960;35(3):358–377.
available from the corresponding author upon reason- 19. Kleiner-Fisman G, Herzog J, Fisman DN, et al. Subthalamic
nucleus deep brain stimulation: summary and meta-analysis of out-
able request. comes. Mov Disord 2006;21(Suppl 14):S290–S304.
20. Krack P, Volkmann J, Tinkhauser G, Deuschl G. Deep brain stimu-
lation in movement disorders: from experimental surgery to
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European Academy of Neurology/Movement Disorder Society-

1360 Movement Disorders, Vol. 37, No. 7, 2022

Movement Disorders, Vol. 37, No. 7, 2022 1361

1362 Movement Disorders, Vol. 37, No. 7, 2022

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with treatment-resistant tremor and those with predom- Summary of Findings

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Movement Disorders, Vol. 37, No. 7, 2022

Movement Disorders, Vol. 37, No. 7, 2022 1367

LCIG for Advanced PD

1368 Movement Disorders, Vol. 37, No. 7, 2022

One recent RCT with a 12-week double-blind phase Radiofrequency Thermocoagulation

Movement Disorders, Vol. 37, No. 7, 2022 1369

1370 Movement Disorders, Vol. 37, No. 7, 2022

Unilateral Lesioning of the STN with MRgFUS

Movement Disorders, Vol. 37, No. 7, 2022 1371

1372 Movement Disorders, Vol. 37, No. 7, 2022

Movement Disorders, Vol. 37, No. 7, 2022 1373

1374 Movement Disorders, Vol. 37, No. 7, 2022

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