ORIGINAL RESEARCH
published: 18 August 2015
doi: 10.3389/fneur.2015.00177
A prospective pilot trial for pallidal
deep brain stimulation in
Huntington’s disease
Lars Wojtecki 1,2 *, Stefan J. Groiss 1,2 , Stefano Ferrea 1,2 , Saskia Elben 1,2 ,
Christian J. Hartmann 1,2 , Stephen B. Dunnett 3 , Anne Rosser 3 , Carsten Saft 4 ,
Martin Südmeyer 1,2 , Christian Ohmann 5 , Alfons Schnitzler 1,2 and Jan Vesper 6 for the
Surgical Approaches Working Group of the European Huntington’s Disease Network
(EHDN) †
1
Edited by:
Antonio Pisani,
Università di Roma “Tor Vergata”, Italy
Reviewed by:
Paolo Calabresi,
Santa Maria della Misericordia
Hospital, Italy
Silmar Teixeira,
Federal University of Piauí, Brazil
*Correspondence:
Lars Wojtecki,
Department of Neurology, Medical
Faculty, Heinrich-Heine-University
Düsseldorf, Moorenstr. 5,
Düsseldorf 40225, Germany
wojtecki@uni-duesseldorf.de
Specialty section:
This article was submitted to
Movement Disorders, a section of the
journal Frontiers in Neurology
Received: 18 June 2015
Accepted: 27 July 2015
Published: 18 August 2015
Citation:
Wojtecki L, Groiss SJ, Ferrea S,
Elben S, Hartmann CJ, Dunnett SB,
Rosser A, Saft C, Südmeyer M,
Ohmann C, Schnitzler A and Vesper J
for the Surgical Approaches Working
Group of the European Huntington’s
Disease Network (EHDN) (2015)
A prospective pilot trial for pallidal
deep brain stimulation in
Huntington’s disease.
Front. Neurol. 6:177.
doi: 10.3389/fneur.2015.00177
Frontiers in Neurology | www.frontiersin.org
Department of Neurology, Centre for Movement Disorders and Neuromodulation, Medical Faculty, Heinrich-Heine-University
Düsseldorf, Düsseldorf, Germany, 2 Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, HeinrichHeine-University Düsseldorf, Düsseldorf, Germany, 3 Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, UK,
4
Department of Neurology, St. Josef-Hospital, Ruhr University, Bochum, Germany, 5 Coordinating Centre for Clinical Trials,
Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany, 6 Department of Stereotactic and Functional Neurosurgery, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany, † Group members are listed in the Author Contributions
section
Background: Movement disorders in Huntington’s disease are often medically refractive.
The aim of the trial was assessment of procedure safety of deep brain stimulation, equality
of internal- and external-pallidal stimulation and efficacy followed-up for 6 months in a
prospective pilot trial.
Methods: In a controlled double-blind phase six patients (four chorea-dominant, two
Westphal-variant) with predominant movement disorder were randomly assigned to either
the sequence of 6-week internal- or 6-week external-pallidal stimulation, or vice versa,
followed by further 3 months chronic pallidal stimulation at the target with best effectside-effect ratio. Primary endpoints were changes in the Unified Huntington’s Disease
Rating Scale motor-score, chorea subscore, and total motor-score 4 (blinded-video
ratings), comparing internal- versus external-pallidal stimulation, and 6 months versus
baseline. Secondary endpoints assessed scores on dystonia, hypokinesia, cognition,
mood, functionality/disability, and quality-of-life.
Results: Intention-to-treat analysis of all patients (n = 3 in each treatment sequence):
Both targets were equal in terms of efficacy. Chorea subscores decreased significantly
over 6 months (−5.3 (60.2%), p = 0.037). Effects on dystonia were not significant over
the group due to it consisting of three responders (>50% improvement) and three
non-responders. Westphal patients did not improve. Cognition was stable. Mood and
some functionality/disability and quality-of-life scores improved significantly. Eight adverse
events and two additional serious adverse events – mostly internal-pallidal stimulationrelated – resolved without sequalae. No procedure-related complications occurred.
Conclusion: Pallidal deep brain stimulation was demonstrated to be a safe treatment
option for the reduction of chorea in Huntington’s disease. Their effects on chorea and
dystonia and on quality-of-life should be examined in larger controlled trials.
Keywords: Huntington’s disease, deep brain stimulation, chorea, pallidum
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Introduction
in terms of their effects on motor function. We also tested the
hypothesis that chronic stimulation of the pallidum would be a
safe and effective treatment first in motor function as chorea,
hypokinesia and dystonia and, second on non-motor aspects as
cognition, emotion, functional disability and quality of life.
Huntington’s disease (HD) is a progressive, motor, cognitive, and
psychiatric neurodegenerative disorder caused by an expanded
CAG repeat in the Huntingtin gene. To date, there is no causal
or disease modifying treatment for HD. The typical motor symptom in HD is chorea, but other movement abnormalities, such
as dystonia and hypokinesia, can occur – especially in juvenile
onset HD (Westphal variant). Although dopamine antagonists
and dopamine-depleting drugs have demonstrated some symptomatic efficacy in patients in whom chorea is the dominant
feature, they often do not produce significant functional improvement. The rationale for using deep brain stimulation (DBS) of
the internal pallidum (GPI) for HD is based on evidence that
GPI–DBS is effective in suppressing non-HD choreiform dyskinesias, such as levodopa-induced dyskinesia (1) in Parkinson’s
disease and the dystonic movements of primary dystonia (2).
Case reports have shown that GPI–DBS has been effective in
various other neurological disorders presenting with choreiform
symptoms [for review, see Ref. (3)]. For the treatment of HDchorea itself, several reports provide preliminary evidence for the
feasibility of pallidal DBS, with reports up to 5 years (4–6). There
might be a better response on chorea rather than on dystonic
symptoms (7). The experience with for Westphal patients is sparse
(8). Some case reports on HD-chorea used blinded assessments (9,
10) but the only prospective two clinical trials evaluating DBS for
choreatic movements (besides levodopa-induced dyskinesias in
Parkinson’s disease) was performed for dystonia–choreoathetosis
in cerebral palsy (11) and recently for HD (12) with the latter however lacking a destinct pre-defined protocol, a controlgroup, blindend assessments, and systematic evaluation of adverse
events.
It is not known whether high frequency internal pallidal stimulation affects cognitive abilities in HD. Most reports do not
identify any changes, however, some decline was noted in two
patients (13). In contrast, motor and cognitive improvements
were reported with stimulation of the external pallidum (GPE) in
animal experiments (14). Further evidence for the usefulness of
GPE stimulation comes from preliminary PET imaging data (15)
of a series of HD patients undergoing GPE–DBS, which showed
decreasing activity and modulation of connectivity within the
basal ganglia-thalamocortical circuit and sensorimotor cortical
areas.
Given this scientific background, it is legitimate to assess pallidal DBS as a treatment option in HD, starting with a prospective
clinical trial assessing its safety and efficacy. About efficacy, in
this prospective 6-months pilot trial, we tested the hypothesis
that randomized GPI and GPE stimulation would be equivalent
Patients and Methods
The trial was designed as a prospective pilot trial focusing on the
safety and efficacy of pallidal DBS in HD. The protocol consisted
of a randomized, controlled crossover design to examine the
hypothesis of the equivalence of GPI and GPE stimulation, and
an uncontrolled 6-month follow-up to assess chronic treatment
effects on movement, cognition, emotion, functional disability,
and quality of life. Timepoints for assessments were based on the
hypothesis that delayed effects were expected.
The trial was monocentric and performed at the Center for
Movement Disorders and Neuromodulation of the HeinrichHeine-University Düsseldorf in Germany. The trial was performed according good clinicial practice, fullfiled the CONSORT
criteria, was registered with ClinicalTrials.gov (NCT00902889)
and approved by the local authorities according to the German
Medical Devices Act (MPG), as well as by the ethics committee of
the Medical Faculty of the Heinrich-Heine University Düsseldorf
(3100). The study was monitored and adverse events were formally reported and evaluated by an independend data and safety
monitoring board (DSMB).
Patients
Six patients with genetically confirmed HD and predominant
motor symptoms were included in the study. All patients gave
written informed consent. Inclusion criteria were: symptomatic
and genetically confirmed HD (CAG repeats >36) for at least
3 years, at least moderate-stage motor symptoms as measured by
≥30 points on the motor component of the Unified Huntington’s
Disease Rating Scale (UHDRS) (16) and failure as measured by
lack of effect or side effects with at least two medical treatments
(tiapride and tetrabenazine mandatory for chorea patients) at the
maximal tolerable dose. Exclusion criteria were: cognitive decline
as measured by fewer than 120 points on the Mattis Dementia
Rating Scale (17) or <80% of motoric performable tasks, major
depression or dominant psychiatric symptoms, previous stereotactic interventions, severe brain atrophy as revealed by MRI scans
(defined as cortical atrophy or atrophy of the pallidum which
rendered planning of a stereotactic trajectory impossible), coagulopathy, immunosuppression, history of cerebrovascular disease,
or cerebral micro- or macroangiopathy, or general medical contraindication to surgery. Inclusion and exclusion criteria were
assessed twice within 3–6 months, prior to final inclusion, to
ensure that included patients had a stable motoric and cognitive
baseline.
Abbreviations: BDI, Beck depression inventory; BFMDRS, Burke-Fahn-Marsden
Dystonia Rating Scale; DBS, deep brain stimulation; GPE, globus pallidus externus,
external pallidum; GPI, globus pallidus internus, internal pallidum; HADS, Hospital
Anxiety and Depression Scale; HD-ADL, Huntington’s Disease Activities of Daily
Living scale; HD, Huntington’s disease; MADRS, Montgomery-Åsberg Depression
Rating Scale; BPRS, Brief Psychiatric Rating Scale; MDRS, Mattis Dementia Rating
Scale; MDS-UPDRS, Movement Disorder Society’s Unified Parkinson’s Disease
Rating Scale; SF-36, Short Form Health Survey; TEED, total electrical energy
delivered; UHDRS, Unified Huntington’s Disease Rating Scale; VTA, volume of
tissue activated.
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Procedure
After assessment of inclusion and exclusion criteria with a stable clinical baseline of at least 3 months (week W–1), patients
underwent presurgical clinical examination. The basic examination (week W0) comprised videotaped motor functions assessed
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Pallidal DBS in Huntington’s disease
according to the UHDRS motor, chorea, and TMS-4 subscores
(16), the motor scores of the Burke-Fahn-Marsden Dystonia
Rating Scale (BFMDRS) (18) and the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS–UPDRS III)
(19). For cognitive and mood assessment the basic test program
contained the Mattis Dementia Rating Scale (MDRS) (17), the
Beck Depression Inventory (BDI) (20), the Montgomery-Åsberg
Depression Rating Scale (MADRS) (21), the Brief Psychiatric
Rating Scale (BPRS) (22) and the Hospital Anxiety and Depression
Scale (HADS) (23). An extended, detailed test program contained:
the UHDRS functional/behavioral assessment, the BFMDRS disability scale, the Huntington’s Disease Activities of Daily Living (HD-ADL) (24) scale, and the Short Form Health Survey
(SF-36) (25).
Surgery was performed in week 0 after baseline assesments
under general anesthesia (propofol, remifentanil). Stereotactic
planning was done by fusion of stereotactic CT with preoperative
MRI (essentially MPRAGE, FLAIR, T2 Space). The trajectory
was planned in such a way that the lowermost contact of the
final electrode would be located in the upper part of the GPI,
while the higher contacts would be positioned in the GPE. For
intraoperative targeting, resting activity of up to five concentric
oriented microelectrodes was recorded. Stimulation of the macro
tip of the recording electrode above and below the target was
done intraoperatively to assess possible major side effects such as
stimulation of the internal capsule.
Medtronic 3387 electrodes (Medtronic Inc., Minneapolis, MN,
USA) were implanted bilaterally and final electrode placement
was verified by a postoperative stereotactic CT. An individualized
visualization of the volume of tissue activated (VTA) was performed with a customized version of Cicerone (26), as previously
described (27).
The electrodes were connected to a subcutaneous implanted
Kinetra impulse generator (Medtronic Inc., Minneapolis, MN,
USA). Five to seven days after surgery (week W0/1) all contacts
were tested for their therapeutic range, using 120 µs pulse width
and 130 Hz frequency as default settings. Stimulation was applied
up to the threshold for side effects, or to the maximum of 5 V.
After first testing, patients were randomized into their treatment
intervention sequence: either stimulation of the two adjacent
lowermost contacts (GPI) for 6 weeks, followed by stimulation
of the two adjacent uppermost contacts (GPE) for 6 weeks, or
vice versa. Thus three of the patients underwent the sequence
GPI–GPE and three underwent the sequence GPE–GPI, during
the first 12 weeks of stimulation. Stimulation was set just below
the threshold for side effects but was intended to cover a broad
anatomic distance of the target area and was thus chosen double
monopolar. On the basis of the clinical best effect-side effect ratio,
the treating physician selected either GPE or GPI stimulation for
further chronic stimulation during the 6-month follow-up.
At preoperative baseline (W0) and 6-month follow-up, the
detailed test battery was performed; for 6- and 12-week GPI/GPE
visits, the basic test program was performed. At all timepoints
tests were performed in the same order. The primary endpoints
were UHDRS motor, chorea and TMS-4 scores for GPI versus
GPE stimulation, and for 6 months versus baseline. Secondary
endpoints were BFMDRS and UPDRS motor scores, cognition
and mood scores, for GPI versus GPE and for 6 months versus
baseline, as well as quality of life and functional assessments for
6 months versus baseline.
Randomization and Blinding
Patients were randomly allocated to the treatment sequence by
the Coordinating Center for Clinical Trials (KKS) Düsseldorf on
the basis of faxed forms filled in by the investigators. The treating physician performed the treatment, and clinical assessments
of scores were performed double-blind by a scoring physician
(directly for rigidity items, video rating for other motor score
items) and a neuropsychologist.
Statistical Analysis
The results were analyzed by intention to treat. Data are reported
as mean (SD) and compared by two-tailed paired Student’s ttests. Kolmogorov–Smirnov test showed normal distribution of
samples. Probability values of 0.05 or less were considered statistically significant. Comparisons were calculated for scores GPI
versus GPE and baseline versus 6 months’ stimulation for primary
and secondary endpoints. Additional subgroup analysis was performed excluding the Westphal variant disease subgroup. Effect
size (Cohen’s d) was calculated for significant differences.
Results
Six patients were included in the trial. All patients were randomly
assigned, resulting in three patients receiving the intended treatment in the sequence GPE-GPI and three patients receiving the
intended treatment in the sequence GPI–GPE. All patients were
analyzed for the primary and secondary endpoint. For a flowchart
of the study see Figure 1. Mean baseline UHDRS motor score was
54.3 with a high SD of 17.6. Two of the patients suffered from the
hypokinetic-rigid Westphal variant of HD. For patient details and
stimulation settings see Table 1. All patients subjectively reported
improvement in daily life with GPI and GPE stimulation and
at 6-month follow-up. The specific group results are reported in
Tables 2–4 and illustrated in Figures 2 and 3.
®
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FIGURE 1 | Flow chart of the study. n = 6, W: week, M: month, dashed
red lines illustrate timepoints of study assessments, red arrows illustrate
calculated comparisons.
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TABLE 1 | A: patient characteristics and B: stimulation parameters with 120 µ s and 130 Hz, two contacts “monopolar” with IPG + except Pat. #2 bipolar
due to limiting side effects.
A
Pat. 1
Pat. 2
Pat. 3
Pat. 4
Westphal variant
Pat. 5
Westphal variant
Pat. 6
Age (years)
52
71
38
25
23
29
Sex
M
F
M
M
M
F
Symptom duration (years)
3
21
10
11
8
4
CAG repeats
17/43
19/41
17/52
19/68
17/70
9/53
Medication (mg)
Amitriptyline (100),
Trospiumchloride (60)
Sulpiride (200),
Ramipril (5),
HCT (25),
L-Thyroxine 75 µg
Tetrabenazine (50),
Tiapride (300)
Quetiapine (37.5),
L-Dopa (300),
Pramipexole (0.54)
Rotigotine (10),
Topiramate (200),
Amantadine (200),
Pantoprazole (40),
Domperidone (30)
Tetrabenazine (25),
Tiapride (300),
Citalopram (40),
Quetiapine (25)
B
Active electrodes
µJ)
TEED (µ
Voltage (V)
Left
Right
Left
Right
Left
Right
Pat. 1
GPI
GPE
6 Month
0−, 1−
2−, 3−
2−, 3−
4−, 5−
6−, 7−
6−, 7−
2.5
2.5
2.5
1.8
2.0
2.2
225
241
148
108
119
131
Pat. 2
GPI
GPE
6 Month
0−, 1−
2−, 3−
0−, 1−
4−, 5+
6+ , 7−
4−, 5+
1.5
3.0
1.5
1.7
2.7
1.7
44
267
44
50
79
51
Pat. 3
GPI
GPE
6 Month
0−, 1−
2−, 3−
0−, 1−
4−, 5−
6−, 7−
4−, 5−
2.0
3.6
2.0
2.0
3.6
1.5
119
355
119
119
521
90
Pat. 4
GPI
GPE
6 Month
0−, 1−
2−, 3−
0−, 1−
4−, 5−
6−, 7−
4−, 5−
1.4
1.7
2.4
1.0
1.7
2.4
42
102
173
30
51
173
Pat. 5
GPI
GPE
6 Month
0−, 1−
2−, 3−
2−, 3−
4−, 5−
6−, 7−
6−, 7−
1.5
2.0
2.0
1.5
2.0
2.0
44
101
120
44
101
92
Pat. 6
GPI
GPE
6 Month
0−, 1−
2−, 3−
2−, 3−
4−, 5−
6−, 7−
6−, 7−
1.4
1.5
1.5
1.2
1.3
1.3
42
44
44
36
39
39
TEED, Total electrical energy delivered in Microjoule (μJ) per second calculated using the formula: Amplitude in Volt (V2 ) × frequency in Hertz (Hz) × pulse width in microseconds (μs) /
impedance in Ohm (Ω). Mean stimulation amplitude: GPI: 1.6 V, GPE: 2.3 V, 6 months: 1.9 V.
Primary Endpoints: UHDRS Motor Score, UHDRS
Chorea Subscore, TMS-4
GPI Versus GPE
8.8 to 3.5 points (−5.3 (60.2%), p = 0.037). The effect on TMS-4
was not significant.
Although GPE stimulation scored slightly better, there was no
significant difference between GPI and GPE stimulation in terms
of motor effects on the UHDRS.
Secondary Endpoints
GPI Versus GPE
There was no significant difference between GPI and GPE stimulation in UPDRS and BFMDRS scores. Cognition and mood did
not differ significantly either.
Six Months Versus Baseline
Based on clinical judgment, three patients (#2, 3, 4) were selected
for chronic GPI stimulation and three (#1, 5, 6) for chronic GPE
stimulation. Analysis of the primary endpoint at 6-month stimulation versus baseline showed a mean difference of 6.1 points
on the UHDRS. Due to a high SD this was not significant (for
individual scores see Figure 3A). However, the UHDRS chorea
subscore decreased significantly over the course of 6 months from
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Six Months Versus Baseline
Effects on dystonia were not significant over the group, however
half the patients (#1, 2, 3) showed marked improvement of more
than 50% on the BFMDRS, with patient #2 showing a decrease
from 19.5 to 3 points (−16.5 (84.7%), see Figure 3B). Further
assessment of mood, cognition, functionality and quality of life
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TABLE 2 | Motor results.
Baseline
A
UHDRS
UHDRS chorea
TMS-4
UPDRS
BFMDRS
B
UHDRS
UHDRS chorea
TMS-4
UPDRS
BFMDRS
GPI
GPE
6 months
p-Value
GPI vs. GPE
p-Value
6 months vs. baseline
Mean
SD
Mean
SD
Mean
SD
Mean
SD
54.3
8.8
37.0
41.3
21.8
17.6
7.5
12.0
23.3
17.4
54.0
5.7
35.5
45.5
24.8
18.1
3.8
13.5
26.1
18.7
50.8
5.2
35.0
48.7
22.7
22.2
4.7
15.6
27.9
21.7
48.2
3.5
32.3
45.8
20.3
24.4
3.2
15.8
28.3
27.0
0.181
0.611
0.611
0.066
0.205
0.160
0.037#
0.135
0.117
0.802
46.5
13.2
32.5
27.2
15.0
15.4
4.0
11.6
8.8
10.8
44.5
8.0
29.0
30.5
15.2
12.9
1.4
11.0
13.8
8.2
39.5
7.7
27.7
32.5
12.0
17.0
3.2
13.2
14.0
10.6
35.0
5.2
24.0
29.0
5.9
15.4
2.2
10.7
13.6
4.5
0.155
0.500
0.368
0.343
0.150
0.016##
0.009###
0.012####
0.523
0.111
A: complete group (n = 6), B: chorea subgroup, Westphal patients excluded (n = 4).
Effect size (Cohen’s d): # 0.919, ## 0.747, ### 2.478, #### 0.762.
TABLE 3 | Results for cognition and mood: Mattis Dementia Rating Scale and subscores (in percent of performable points), BDI, MADRS, BPRS, HADS-D.
Baseline
A
Mattis Total score
Mattis Attention
Mattis Concentration
Mattis Visuoconstruction
Mattis combinatoric
Mattis memory
BDI
MADRS
BPRS
HADS-D
B
Mattis total score
Mattis attention
Mattis concentration
Mattis visuoconstruction
Mattis combinatoric
Mattis memory
BDI
MADRS
BPRS
HADS-D
GPI
GPE
6 months
p-Value
GPI vs. GPE
p-Value
6 months vs. baseline
Mean
SD
Mean
SD
Mean
SD
Mean
SD
88.2
88.7
76.0
100.0a
97.4
89.3
7.1
6.7
14.4
0.0a
2.8
7.4
86.7
89.6
70.0
100.0b
97.4
87.3
8.0
6.3
17.0
0.0b
2.8
13.5
86.5
89.6
72.1
100.0b
96.1
85.3
9.0
7.1
18.2
0.0b
4.5
11.2
86.9
86.9
71.4
100.0b
97.4
90.7
7.4
7.3
15.8
0.0b
2.8
7.9
0.849
1.000
0.493
*
0.203
0.456
0.213
0.328
0.027#
*
*
0.530
3.00
3.83
21.67
3.50
5.02
5.08
4.50
5.82
3.83
3.17
21.00
3.50
6.15
2.40
2.10
4.59
2.60
2.83
21.00
3.60
2.70
3.49
3.52
5.68
0.402
0.684
0.586
1.000
0.230
0.081
0.063
0.04##
0.342
0.664
0.161
*
0.391
0.182
0.693
0.789
0.168
*
*
0.495
0.102
0.432
0.516
0.824
0.299
0.249
0.104
0.093
6.60c
7.50
26.17
7.60
91.4
91.9
82.2
100.0
98.7
91.0
7.63 c
7.97
8.56
8.08
6.6
5.8
13.8
0.0
2.6
7.6
7.50
9.00
29.00
8.75
8.50
9.76
9.42
8.85
90.4
91.9
77.0
100.0
98.7
93.0
3.75
5.00
22.75
5.25
6.2
6.6
15.7
0.0
2.6
8.9
6.18
6.00
5.25
6.65
91.3
93.2
82.4
100.0
98.1
89.0
5.2
4.7
10.2
0.0
3.8
11.5
5.50
3.25
21.50
5.00
7.19
2.99
2.38
5.10
90.8
91.2
79.0
100.0
98.7
93.0
3.00
4.25
22.25
4.50
5.4
4.0
13.5
0.0
2.6
3.8
2.94
3.50
3.77
6.14
A: complete group (n = 6), B: chorea subgroup, Westphal patients excluded (n = 4).
Data from 3, 4, or 5 patients; *cannot be calculated.
Effect size (Cohen’s d): # 0.304, ## 0.573.
a,b,c
revealed the following change from baseline at 6-month followup: cognition was stable as measured by Mattis, although a slight
but significant deterioration was noted in tests of concentration,
from 76.0 to 71.4% (p = 0.027). In accordance with the exclusion
criteria, patients showed normal mood and psychiatric scores at
baseline, however HADS-D (depression) improved significantly
(p = 0.044), and MADRS and BPRS showed a statistical trend
toward improvement. Several items in the quality of life and
functional assessments showed significant improvement, such as
the SF-36 vitality and mental health scores, while others showed a
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statistical trend toward improvement (SF-36 social role functioning score, UHDRS behavioral assessment).
Subgroup Analysis
Post hoc analysis of the choreatic subgroup of patients (nonWestphal, n = 4) for the primary endpoints showed no significant difference between GPI and GPE stimulation. At 6-month
follow-up the primary endpoints showed significant results: the
UHDRS showed a significant decrease: from 46.5 to 35.0 points
(−11.5 (24.7%), p = 0.016). For the chorea subscore the difference
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Mean
SD
Mean
SD
12.0
8.7
12.7
9.7
0.465
UHDRS functional
assessment
5.2
3.9
6.7
5.5
0.237
between baseline and 6 months was highly significant: 13.5 compared to 5.2 points (−8 (60.6%), p = 0.009). The TMS-4 also
showed a significant decrease, from 32.5 to 24.0 points (−8.5
(26.2%), p = 0.012). Concerning secondary endpoints in the nonWestphal subgroup the BFMDRS disability score improved significantly and the HD-ADL and SF-36 mental health score showed a
trend toward improvement.
In the secondary motor endpoints the Westphal patients (#4, 5)
showed no improvement in dystonia (BFMDRS) or hypokineticrigid symptoms (UPDRS) with GP stimulation.
UHDRS behavioral
assessment
8.0
4.6
4.2
5.3
0.057
Medication
HD-ADL
28.6a
11.0a
21.2a
16.6a
0.227
BFMDRS disability
scale
14.2
7.8
13.0
8.9
0.302
SF-36 physical
functioning
30.83
29.9
38.3
40.6
0.620
SF-36 physical role
function
54.2
40.1
58.3
51.6
0.793
SF-36 bodily pain
66.7
51.6
81.7
40.2
0.648
SF-36 general health
perception
63.0
21.5
79.2
12.7
0.169
SF-36 vitality
48.3
12.1
70.8
23.1
0.030#
SF-36 social role
functioning
52.2
25.5
77.3
30.8
0.090
SF-36 emotional role
functioning
72.2
44.4
77.8
40.4
0.788
SF-36 mental health
B
UHDRS functional
capacity
69.3
13.3
90.7
13.3
0.022##
Mean electrode localization is provided in Figure 4. Furthermore,
images of individual electrodes with volume of tissue activated
(VTA) are shown in Figure 5. Mean coordinates with reference to
the midcommissural point [x, y, z (SD)] were: 21.8 (2.1), 3.8 (1.0),
−3.6 (2.4) for GPI; 22.9 (2.0), 5.9 (1.2), 2.4 (3.2) for GPE; and 22.4
(2.0), 4.8 (1.8), 0.2 (5.6) for stimulation at 6-month follow-up. In
summary, the mean stimulated area at 6 months was located in
projection to the laminal border zone between the internal and
external pallidum.
16.0
7.4
17.5
7.8
0.215
Adverse Events
UHDRS functional
assessment
6.5
4.0
9.2
4.9
0.102
UHDRS behavioral
assessment
8.5
4.8
5.5
6.1
0.245
HD-ADL
25.3
6.7
10.7
7.0
0.080
BFMDRS disability
scale
10.2
4.7
7.7
3.9
0.030#
SF-36 physical
functioning
42.5
30.1
57.5
35.7
0.525
SF-36 physical role
function
56.2
51.5
75.0
54.0
0.319
SF-36 bodily pain
50.0
57.7
75.0
50.0
0.638
SF-36 general health
perception
68.5
7.0
76.5
15.4
0.380
SF-36 vitality
47.5
13.2
66.2
28.1
0.141
SF-36 social role
functioning
56.2
31.4
66.0
32.7
0.430
SF-36 emotional role
functioning
58.2
50.0
75.0
50.0
0.602
SF-36 mental health
61.0
3.8
87.0
15.4
0.063
TABLE 4 | Results for activity of daily living and quality of life.
Baseline
A
UHDRS functional
capacity
6 months
p-Value
6 months vs.
baseline
Medication for motor treatment was kept stable throughout the
trial in most patients. In one patient (#2), sulpiride was reduced
from 200mg to 100mg after the operation, while in another
(#3), tetrabenazine (50mg) and tiapride (300mg) were completely
withdrawn after the operation.
Electrode Localization and Volume of Tissue
Activated
No procedure-related complication such as bleeding occurred.
Eight adverse events were recorded: possibly related to treatment:
bradykinesia (GPI), hyperthermia possibly related to stimulation due to stable medication (GPI, Westphal), gait impairment
and fall (GPI 6 month), increased chorea after reprograming due
to bradykinesia (GPI 6 month); possibly related to stimulation
system: deactivation of impulse generator (GPE); unrelated to
stimulation but possibly due to hospitalization: thrombophlebitis
(W0 postop), MRSA nose infection (W0 postop), superficial nose
abrasion (GPE). In addition, two serious adverse events were
reported: gait impairment and hyperkinesia after reprograming
(GPI 6 month, Serious Adverse Event (SAE) criterion: leading to
hospital admission and requiring reprograming) and postoperative (W0 postop) malignant hyperthermia possibly related to stimulation due to stable medication (SAE criterion: life-threatening
and leading to prolonged hospital stay). All stimulation-related
adverse events occurred under GPI stimulation. All adverse events
resolved without sequalae.
Individual Patient Discription
For individual motorscores please see Figure 3. For individual
electrode localization please see Figure 5.
Patient 1 is a patient with predominant choreatic and dystonic
trunk-movements that impacted his quality of life. Although
the chorea sum-score was below 10 points he had benefit from
DBS. Dystonic movements also improved. GPE stimulation
a
Data from five patients.
A: complete group (n = 6), B: chorea subgroup, Westphal patients excluded (n = 4).
SF-36, UHDRS functional capacity, functional assessment: increase = improvement.
BFMDRS disability scale, HD-ADL, UHDRS behavioral assessment, care giver rating:
decrease = improvement.
Effect size (Cohen’s d): # 1.22, ## 1.609.
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A
C
B
FIGURE 2 | Percent change improvement from baseline of primary endpoints. Mean with SD (error bars) and individual results (A): UHDRS, (B): TMS-4,
(C): UHDRS chorea subscore, note: chorea subscore could only be calculated for four patients (non-Westphal). **Significant change from baseline, p < 0.01.
A
B
75
75
60
Pat. 1
Pat. 2 §
60
Pat. 3 §
Pat. 4 §
BFMDRS
UHDRS
45
45
Pat. 5
Pat. 6
30
30
15
15
0
Base
GPI
GPE
6 months
Base
GPI
GPE
6 months
FIGURE 3 | Individual motor score changes. Individual UHDRS (A) and BFMDRS (B) at baseline, with GPI, GPE and chronic 6-month stimulation [Pat. #1, 5, 6
GPE; Pat. #2, 3, 4 GPI (§)]; Westphal patients: gray lines, #4, 5. Note: GPI/GPE sequence was randomized with GPI first in Pat. #1, 4, 5 and GPE first in Pat. #2, 3, 6.
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Thus, mean chronic stimulation at 6-month follow-up projects mid-electrode to
the border zone between GPE and GPI. For visualization the following atlas
software was used: Medtronic DBS Neurosurgical Simulator, licensed 2008,
Version 1.2.3, Medtronic Inc., Minneapolis, MN, USA.
FIGURE 4 | Mean electrode localization. Visualization of mean coordinates
of left and right hemisphere mirrored to the left; 3D space relative to AC-PC line
(green dot: AC, red dot: PC), gray mash: GPI, green mash: GPE; lowermost
contacts comprise GPI and uppermost contacts comprise GPE stimulation.
FIGURE 5 | Individual electrode localization. Visualization on 3D coronary MRI-view of individual electrodes and volume of tissue activated (VTA, in red) in relation
to the pallidum (in brown) for the ventral target (GPI), the dorsal target (GPE) and the target at 6-month follow-up.
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was slightly more effective than GPI stimulation. Patient 2 had
generalized chorea. She suffered from postural instability due
to anti-chorea drug treatment before surgery. With DBS chorea
suppression was possible with minor impairment of balance. GPI
and GPE stimulation was similar in terms of chorea reduction.
GPI stimulation was better tolerated and chosen for chronic
stimulation. The narrow therapeutic window between brady- and
hyperkinesia remained a difficult issue resulting in two adverse
events of reprograming (bradykinesia, increased chorea). Dystonia also markedly improved in this patient at 6 month follow-up.
Patient 3 showed improved chorea and dystonia, however this
effect was seen mainly at 6 month follow-up. GPI stimulation
was chosen for chronic stimulation. Stimulation-induced gait
impairment led to a SAE in this patient. Patients 4 and 5 suffered
from the Westphal variant with strong bradykinesia and dystonia.
Although objectively no improvement could be observed in the
scores, the caregiver reported improved dystonia of the neck.
Both Westphal patients had issues with (S)AE (pneumonia
and hyperthermia). Patient 6 had marked improvement of her
generalized chorea especially with GPE stimulation. Before
surgery, she had frequent falls with bone fractures due to drug
treatment that could be stopped after surgery.
comparison between baseline and GP stimulation at 6 months, we
still observed remarkable reduction of chorea (60.2%), statistically
however with a p-value (p = 0.037) just below the threshold of
significance.
Although both the patients and the scoring physician were
blinded according to the destinct stimulation site, the prospective
design did not include a placebo control group, which means
blinding concerning active treatment in general. At the current
state, we can not rule out a bias by placebo responses and emotional state especially on chorea and quality of life. Both these
limitations – the small sample size and the lack of a placebo control
group – should be examined further in a larger trial. Given the
authors’ experience with trials on other hyperkinetic disorders
such as dystonia (2), a placebo sham stimulation controlled trial
will be the next reasonable step rather than arguing in favor of
an ON–OFF (crossover) design of a trial. Thus, a multi-center
trial that randomizes patients directly after surgery blinded either
into the stimulation ON or OFF group and assesses clinical effects
after 3 months has just started. This design can control for lesion
and placebo effects directly after the surgical intervention, which
would not be the case for a crossover ON vs. OFF phase during
the trial.
Some technical aspects of the design could have further biased
the results. For safety reasons, we chose to implant only one
electrode per hemisphere. Thus, more ventral “internal” and more
dorsal “external” pallidal stimulation was achieved by contact programing. Although electrode targeting was adjusted accordingly,
for anatomical reasons it is not possible to stimulate both the
most ventral GPI and the most dorsal part of the GPE with one
electrode. As we did not find it justified to implant four electrodes
and in order to make the electrode position suitable for a crossover design of GPI versus GPE stimulation, we implanted the
electrodes slightly more dorsal than the usual GPI target point.
One has to be aware that this approach might have biased the
results. Furthermore, the fact that we used double-monopolar
stimulation might have biased the spatial discrimination of effects
between GPI and GPE target areas.
We calculated the mean contact position of the chronic stimulation at 6 months virtually, and visualized it on an atlas in the
border zone between the GPI and GPE. Brain atrophy makes
it hard to judge the exact electrode position with respect to
the pallidum in HD patients. However, we furthermore provide
individual electrode scans together with calculation of volume of
tissue activated (VTA) of the patients.
To standardize stimulation parameters as much as possible,
we worked with fixed frequencies and pulse widths. Thus, we
are not able to answer questions concerning frequency effects
with this study. Besides worsening of hypokinesia with high frequency stimulation of more than 130 Hz, some reports have noted
improvement of chorea with minor worsening of hypokinesia
at 40 Hz, suggesting that frequency settings might play a major
role (10). This fits with our long-term clinical experience (28).
However, there have been other reports of more heterogeneous
outcomes with 40Hz (13), and even worsening of chorea (29).
Besides stimulation frequency, the period of chronic application
of stimulation can be of importance. We chose a period of 6 weeks
of chronic stimulation to compare GPI with GPE. Although some
effects on chorea could be observed within minutes, we cannot
Discussion
This is the first prospective trial for DBS in Huntington’s disease according to the CONSORT criteria following a predefined
protocol using a controlled phase and blinded assessments of
primary endpoints and with full reporting of adverse events under
monitoring of a DSMB. The data provide preliminary evidence
that DBS electrode implantation can be performed in a safe procedure with no procedure-related side effects. Moreover, primary
endpoint analysis showed that: (1) external pallidal stimulation
was equivalent to internal pallidal stimulation; and (2) chronic
stimulation of the pallidum was effective in terms of significant
reduction of chorea over 6 months in patients comprising large
effect sizes. Secondary endpoint analysis showed that effects on
dystonic symptoms varied inter-individually from no response
to a strong response. Hypokinetic-rigid symptoms and Westphal
patients did not improve. Cognition was generally stable over
6 months. Several measures of quality of life and functionality
improved significantly, as did measures of mood. Electrode localization revealed that mean chronic stimulation at 6-month followup was applied in the GPI/GPE border zone.
The strengths of the current study are: the prospective design,
the double-blinded assessment of the GPI- versus GPE-phase,
and the examination of the effects and side-effects of chronic
stimulation on non-motor aspects of HD, as well as on quality of
life. On the basis of these preliminary results, it can be concluded
that pallidal DBS is a potential treatment option for chorea in HD,
and should be further examined in larger, multicentric, placebocontrolled trials.
Limitations of the current study should be noted. Due to the
pilot, monocentric nature of the trial, sample size was limited,
meaning that the finding of equivalent efficacy for GPI and
GPE, in particular, could be underpowered. Furthermore, one
has to be aware of the limits of statistical validity with a small
sample size. Despite the small sample size for the open label
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rule out that some treatment effects were missed due to the short
period of stimulation. Note that several patients showed greater
improvement on the UHDRS at 6 months than at any of the 6week assessments. This observation speaks in favor of a chronic
(neuroplasticity) effect of stimulation that outweighs clinical disease progression, and against a strong placebo effect. Increased
treatment effect over time seems not be caused by stimulation
strength as amplitudes at 6 months were similar to the mean of
GPI and GPE stimulation at 12 weeks.
Concerning the generalizability of our findings, we think it is
appropriate to conclude that chronic pallidal DBS should be considered as a treatment option for choreatic forms of HD. Patients
without significant chorea seem not to benefit from pallidal DBS.
It is, however, questionable whether our negative findings in
Westphal patients can be generalized. Not only was the Westphal
group too small to generate results of any significance, but the
two Westphal patients suffered from the highest number of CAG
repeats and the highest UHDRS scores. It is possible that the lack
of effect we observed in the Westphal subgroup was due to the
stage of the disease rather than to the motor phenotype (dystonia
and mainly bradykinssia) itself. On the other hand, the bradykinetic phenotype might have profited more from subthalamic or
posterior-ventral pallidal stimulation rather than from the chosen
dorsal GPI/ventral GPE stimulation. Correlations of treatment
effect with CAG repeats, UHDRS scores at baseline and burden
of disease scores should be calculated in future larger trials. In the
current study, the sample size was too small to allow calculation
of proper correlations. A larger sample size will probably also
shed light on predictors of non-response with respect to dystonic
symptoms. Although the effects were not significant over the
group, the current study shows that effects can be large, thus
corroborating earlier findings for DBS in HD (10).
The final interpretation of our results must include a discussion
of the harm-benefit ratio of this invasive treatment. It is important
to note that the implantation procedure itself was safe. Adverse
events were mainly related to stimulation. In line with previous
findings and expected under high frequency stimulation [e.g.,
see Ref. (9)], we found that internal, as opposed to external,
pallidal DBS can incur side effects such as gait problems and
bradykinesia. Although the beneficial treatment effects did not
differ significantly between GPI and GPE stimulation, the slightly
larger improvement in motor scores, combined with the lower
risk of side effects and higher tolerated stimulation amplitudes
and TEED, seen with GPE stimulation, speak in its favor. Overall,
cognition was stable across the group, however the cognitive
subscore “concentration” deteriorated slightly, and no cognitive
improvement was seen. In addition, due to the effect-side effect
ratio, it might be reasonable to choose GPE stimulation for a larger
trial, in order to try to achieve the improvement in cognition that
has been reported in animal experiments (14). The results of the
current trial suggest that it could also be reasonable to expect
effects on quality of life in a larger trial, because even in this small
sample, subscores showed significant improvement. However, as
some of significant non-motor effects got lost in the non-Westphal
group despite motor improvement a considerable higher number
of patients will be needed to show stable results on quality of
life.
In summary, it might be promising to further examine pallidal
DBS concerning the question if it is an effective and safe treatment
option for HD patients with severe chorea. Its effects on other
outcome measures such as dystonia and non-motor aspects of the
disease should also be examined in a larger trial.
Author Contributions
LW, SG, AS, CO, SD, AR, CS, JV: study design and/or clinical management; LW, SG, SF, SE, SR, CH, MS: data acquisition of videos
and clinical scores; SG: blinded video rating; LW, SF: clinical data
analysis; LW, CH, JV: data analysis of electrode contacts; LW, AS,
JV: drafting of the manuscript. All authors: revision and approval
of the manuscript.
Members of the EHDN surgical approaches working group
in preparation and during the trial were: A. Rosser – Cardiff,
UK (Chair); S. B. Dunnett – Cardiff, UK (Co-Chair); J. Vesper – Düsseldorf, Germany (Co-Chair); L. Wojtecki – Düsseldorf,
Germany; H. Lange – Dinslaken, Germany; C. Saft – Bochum,
Germany; R. Reilmann – Münster, Germany; S. Piacentini –
Florence, Italy; A. Fasano – Rome, Italy; V. Visser-Vandewalle –
Maastricht, Netherlands; Y. Temel – Maastricht, Netherlands; P.
Krystowiak – Amiens, France.
Acknowledgments
We thank the following persons for organisational and statistical support: M. Biernat, M. Blicke, S. Rödel (Department of
Neurology and Institute of Clinical Neuroscience and Medical
Psychology Düsseldorf); G. Felder, Q. Yang, M. Partowinia-Peters
(Coordinating Centre for Clinical Trials (KKS) Düsseldorf); C.
Schade-Brittinger (Coordinating Centre for Clinical Trials (KKS)
Marburg). We thank Cameron C. McIntyre for giving us the
opportunity to calculate VTA with his tools. We thank the medical
writer Laura Spinney for lecturing the manuscript. We thank the
patients for their participation. Trial Registration: The trial was
registered in ClinicalTrials.gov (NCT00902889). Funding: The
study was sponsored by a seed fund from the European Huntington’s Disease Network (EHDN). The funding source of the EHDN
itself, represented by the Scientific and Bioethics Advisory Committee (SBAC), had no role in the study design, data collection,
data analysis, data interpretation or writing of the report. EHDN
sponsored the medical writer for lecturing the manuscript. The
surgical approaches working group of the EHDN contributed to
the study design. The corresponding and senior authors had full
access to all the data and final responsibility for the decision to
submit the paper for publication.
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Conflict of Interest Statement: Lars Wojtecki, Jan Vesper, Alfons Schnitzler, and
Martin Südmeyer received consultant honoraria and travel grants from Medtronic.
The remaining authors have no conflict of interest to declare.
Copyright © 2015 Wojtecki, Groiss, Ferrea, Elben, Hartmann, Dunnett, Rosser, Saft,
Südmeyer, Ohmann, Schnitzler, Vesper and the Surgical Approaches Working Group
of the European Huntington’s Disease Network (EHDN). This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution
or reproduction is permitted which does not comply with these terms.
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August 2015 | Volume 6 | Article 177