Gruber et al., Supplementary appendix
SUPPLEMENTARY APPENDIX
Quadruple deep brain stimulation in Huntington´s disease, targeting pallidum and subthalamic nucleus deep: case report and review of the literature.
D Gruber, AA Kuehn, T Schoenecker, UA Kopp, A Kivi, J Huebl, E Lobsien, B Mueller, G-H Schneider, A Kupsch
METHODS
Surgical Procedure
The pallidal target point was located 20 mm lateral to the midline, 4 mm below the intercommissural line, and 3mm anterior to the midcommissural point. Target localisation for STN was 12 mm lateral of the AC–PC line, 2–3 mm behind the midcommissural point, and 4–5 mm below the AC–PC line.
Target points were based on direct target visualization on preoperative MRI and verified intraoperatively using microelectrode recording, macrostimulation with evaluation of motor effects, adverse events (induction of phosphenes), and long-distance biorthogonal x-ray. Postoperatively, an individual MRIs (1.5T MRI scanner, NT Intera, Philips, The Netherlands) was performed (Weise et al. 2010).
One week following implantation of four DBS-electrodes GPi-leads were connected with an impulse generator (IPG) Kinetra® in the right subclavicula region. Six months later STN-electrodes were connected with IPG Kinetra® in the left subclavicular region for treatment of bradykinesia despite optimized GPi-DBS. No device induced adverse events were detected.
Neuropsychology, Affective State and Quality of Life
For neuropsychological screening Mattis Dementia Rating Scale (MDRS) and the MWT-B, a German equivalent of the National Adult Reading Test estimated the premorbid verbal intelligence, were used. To investigate alertness Trail making test was performed. Visuo-perceptive and visuo-constructive functions were evaluated by using Visual Object and Space Perception Battery (VOSP) and mosaik test HAWIE-R. Boston Naming test were obtained to assess speech, the Rey-Osterrieth Complex Figure (RCF), Rey Auditory Verbal Learning Test (RAVLT) and digit span to investigate learning and memory. Executive function and problem solving were examined by Stroop interference part, fluency, planning test, trail making test and Leistungsprüfsystem (LPS) (Lezak 1995; Sturm 1993).
To investigate the health-related quality of life the Medical Outcomes Study 36-item Short-Form General Health Survey (SF 36) was employed (Bullinger 1996). The eight different dimensions of health-related quality of life (self-reporting generic scale) can be accumulated to physical and mental summary subscores ranging from 0 to 100, where a score of 0 indicating the worst and a score of 100 the best possible state.
Furthermore Questions on life satisfaction (QLS) were applied including general life satisfaction and satisfaction with health concerning movement disorder (QLS-MD) and DBS (QLS-DBS), higher scores reflect more life satisfaction (Kuehler et al. 2003). Functional capacity was estimated by Quantified Staging of Functional Capacities (Shoulson et al. 1989).
Beck depression inventory (BDI) (Beck et al. 1961), Beck anxiety inventory (BAI) (Beck and Emery 1985), Montgomery Asberg Depression Scale (MADRS) (Montgomery and Asberg 1979), Brief Psychiatric Rating Scale (BPRS) and Bech-Rafaelsen Mania Rating Scale (BMRS), Snaith-Hamilton-Pleasure-Scale (SHAPS) and Positive and Negative Syndrom Scale (PANSS) served to estimate neuropsychiatric status (Kay et al. 1987).
RESULTS
Individual Programming Strategies
Following implantation of IPG GPi-DBS was started with monopolar stimulation parameters, i.e. testing of all contacts at 130 Hz, 90 μs, voltage level below side effects (Kupsch et al. 2011). After 3 months due to increased bradykinesia frequency was lowered to 40 Hz GPi-DBS. Because of inconsistent antichoreatic effects and increased bradykinesia with 130 Hz GPi-DBS (table 1 at 3mths postsurgery: UHDRS bradykinesia subscore presurgery/3months postsurgery 15/24), STN-IPG was connected and STN-DBS was initiated 9 months postsurgery, firstly in monopolar condition and subsequentely due to side effects with bipolar stimulation settings with standard stimulation parameters for STN-DBS (130 Hz, 60 μs). At the 1 year visit increased chorea was noted, and DBS-OFF state for 4 days was assessed (table 1) for systematic readjustment of DBS-parameters. After turning off IPG chorea and gait disturbances with danger to fall reappeared. Best results for chorea and bradykinesia were achieved with combined high voltage, bipolar STN-DBS and low voltage, monopolar GPi-DBS.
Two years postsurgery due to insufficient antichoreatic effects and side effects following voltage elevation, DBS of STN and GPi was switched off again for 4 days. Single contacts and different frequency conditions of GPi- and STN-leads were systematically tested again (table 2). Combined STN-GPi-DBS following adaption of frequency and monopolar stimulation mode of STN was chosen up to the next visit.
At 3 years follow up substantially increased postural instability was observed with danger to fall, which was improved by reducing frequency of STN-DBS from 80 Hz to 70 Hz. Testing of OFF conditions was refused by the patient at this time, since the slight increase of chorea and bradykinesia compared to former visits, did not influence patient mobility and subjective satisfaction of the patient.
Four years postsurgery a reprogramming was neccessary due to increased chorea of upper extremities. Elevation of voltage level did not lead to reduction of chorea, but rather increased bradykinesia and postural instability. Changing monopolar to bipolar setting of GPi-DBS impoved chorea without adverse affects. Interstingly, voltage levels up to 3.0 V were tolerated, which were not tolerated in the former years due to adverse effects.
Discussion
Effects depending on localization
Interestingly, ventral STN-DBS lead to distinct impairment with increased chorea, postural instability, gait disturbance and dysarthria. STN-DBS via proximal contacts located close to pallidofugal fiber tract and activation of GPi-contacts targeted nearby GPe border improved both chorea and hypokinesia. Pathophysiological explanations for the apparent paradox of the coexistence of chorea and bradykinesia suggest an involvement of direct and indirect pathways (Marsden and Obeso 1994).
Although in open observational studies (e.g.(Volkmann et al. 2004)) the antibradykinetic effects of GPi-DBS may be less prominent in PD compared to STN-DBS, GPi-DBS or STN-DBS equally improved bradykinesia and levodopa induced dyskinesias in PD-patients in more rigerous trials (Follett et al. 2010). Interestingly, GPi-DBS in HD has been reported to slightly improve or - as in our case - deteriorate bradykinesia (cf. table 1). Conceivably, these opposite results may reflect differing positions of active contacts in GPi or, more importantly, different pathophysiologies in these two neurodegenerative diseases, which is supported by diverging GPi neuronal firing patterns in HD and PD patients (Tang et al. 2005).
Time course of disease and treatment
In our patient, improvement of chorea and bradykinesia seemed to be more pronounced in the first year compared to third and fourth year postsurgery, possibly reflecting disease progression. Interestingly, during first and second year visits the patient seemed to present no disease progression following 4 days DBS-OFF compared to presurgical state. However, at the fourth year withdrawal of DBS induced severe generalized chorea which necessitated switching on the IPGs after 45 minutes. Although a rebound phenomenon can not be excluded (Bittar et al. 2005), this aggravation of off-chorea in the fourth year is likely to reflect disease progression, since similar off-deterioration had not been observed in the first two years. Notably DBS-induced improvements on chorea were similar either at 1, 2, 4 years as reflected by approximately 50-60% amelioration of ON/OFF- DBS-scores (table 2).
In accordance with beneficial effect of STN-DBS in PD (Follett et al. 2010; Schuepbach et al. 2013) we observed an amelioration of both bradykinesia between 10-60% depending on time course and stimulation parameters as well as chorea following separate bipolar STN-DBS. At 4 years postsurgery increased chorea was only attenuated following combined GPi-STN-DBS at the expense of increased bradykinesia. Additionally, GPi-DBS was necessary due to insufficient antichoreatic effects of separate STN-DBS.
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Supplementary table 1. Cognitive evaluation pre- and postsurgery
Test / Baseline / 3months / 1 year / 2 years / 3 years / 4 yearsMattis Dementia Rating Score (0-144)
Alertness (0-37)
Perception (0-37)
Construction (0-6)
Combination (0-39)
Memory (0-25) / 143
37
37
6
39
24 / 140
36
35
6
38
25
Rey Auditory Verbal Learning Test
Total Score (0-75)
Delayed recall (0-15)
Recognition correct (0-15) / intrusions / 29 (PR <5)
3 (PR <5)
14/11 (PR <5) / 28 (PR <5)
4 (PR <5)
12/8 (PR <5) / 32 (PR <5)
5 (PR <5)
15/4 (PR 5) / 24 (PR <5)
3 (PR <5)
12/5 (PR <5) / 25(PR <5)
3(PR <5)
11/6 (PR <5) / 25(PR <5)
3(PR <5)
11/5 (PR <5)
Rey-Osterrieth Complex Figure
Copy (errors)
Reproduction
Delayed recall / 0
30 (PR 95)
31 (PR 96) / 0
31 (PR 98)
33 (PR 99) / 0
24 (PR 62)
24 (PR 62) / 0
30 (PR 95)
30 (Pr 95) / 0
30 (PR 95)
28 (PR 92) / n.a.
Digit span
forward (0-12)
backward (0-12) / 6 (PR 18)
4 (PR 5) / 5 (PR 8)
6 (PR 30) / 6 (PR 18)
7 (PR 58) / 6 (PR 18)
6 (PR 30) / 2 (PR <2)
5 (PR 12) / 4 (PR <2)
6 (PR 30)
Stroop Interference (in sec.)
Stroop Interference/ errors / 170 (PR 10)
1 / 240 (PR <1)
0 / 263 (PR <1)
0 / 296 (PR <1)
0 / 348 (PR <1)
0 / 425 (PR <1)
0
Trail Making Test (in sec.)
Part A
Part B
Part B-A / 44
155
111 / 42
140
98 / 58
108
90 / 70
144
74 / 45
155
110 / 49
160
111
Semantic fluency (RWT) / 18 (PR 12) / 17 (PR 7) / 16 (PR 6) / 22 (PR 33) / 18 (PR 23) / 12 (PR 1)
ToL (minimal no. of moves = 33) / 36 (PR 50) / 35 (PR 70) / 36 (PR 50) / 36 (PR 50) / 43 (PR 2) / n.a.
Boston Naming Test (of 15) / 14 / 15 / 15 / 15 / 15 / 14
HAWIE-R Block Design / 26 (WP 9) / 25 (WP 8) / 27 (WP 9) / 28 (WP 10) / 26 (WP 9) / n.a.
LPS, Subtask 3: reasoning / 21 (PR 50) / 25 (PR60) / 25 (PR 60) / 23 (PR 50) / 23 (PR 50) / 18 (PR 45)
VOSP
Screening (cut-off 15)
Object Perception
Incomplete Letters (cut-off <17)
Silhouettes (cut-off <16)
Object Decision (cut-off <15)
Progressive Silhouettes (cut-off >14)
Space Perception
Dot Counting (cut-off <8)
Position Discrimination (cut-off <18)
Number Location (cut-off <7)
Cube Analysis (cut-off <6) / 20
20
24
20
13
8
18
9
10 / 20
20
23
17
13
10
19
9
9 / 20
20
23
17
12
10
19
9
9 / 20
20
23
17
10
10
20
10
10 / 20
20
20
17
9
10
20
10
10 / 20
19
25
16
6
10
19
9
10
Supplementary table 1. Neuropsychological data. Baseline evaluation revealed a dysexecutive syndrome comprising impairment of attention, short term and working memory, and of planning and interference capacity. Furthermore, anterograde verbal memory deficit could be observed in contrast to normal visual memory. Visuo-perceptive and visuo-constructive functions were normal. Four years postoperatively executive functions comprising planning, interference capacity and working memory were moderately decreased. Abbreviations: PR = percentile ranks, z = standard scores, RAVLT = Rey Auditory Verbal Learning Test, ROCF = Rey-Osterrieth Complex Figure Test, RWT (Regensburger Wortfluessigkeitstest), HAWIE-R = Hamburg Wechsler Intelligenztest fuer Erwachsene-Revidierte Fassung (German version of the Wechsler Adult Intelligence Scale-Revised), ToL = Tower of London, LPS = Leistungsprüfsystem, VOSP = The Visual Object and Space Perception Battery, n.a. = not assessed
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Supplementary table 2. Quality of life and affective state
Baseline / 3mths / 1yr / 2yrs / 3yrs / 4yrs / Age-matchedstandard values
Quality of life and life satisfaction
SF 36
Physical summary subscore (0-100)
Mental summary subscore (0-100)
Questions on life satisfaction (QLS)
General life satisfaction (-96-160)
Satisfaction with health (-96-160)
QLS-Movement Disorder (-144-240)
QLS-Deep Brain Stimulation (-60-100)
Quantified Staging of Functional Capacities (0-13) / 33
34
93
-4
-68
n.a.
6 / 44 é
30 ê
150 é
0 é
60 é
100
6 / 43 é
44 é
24 ê
24 é
36 é
57 ê
6 / 39 é
43 é
160 é
160 é
240 é
52 ê
6 / 27 ê
49 é
107 é
112 é
0
60 ê
7 / 20 ê
59 é
n.a.
7 / 51,4±9,6
52,4±7,7(Bullinger 1996)
62,8 ± 38.6 (age 36-45)
80,8 ± 37.8 (age 36-45)
not available
not available (Henrich and Herschbach 2001)
Affective state
Beck Depression Inventory (BDI, 0-63)
Beck Anxiety Inventory (BAI, 0-63)
Montgomery Asberg Depression Rating Scale (MADRS, 0-60)
Snaith-Hamilton-Pleasure-Scale (SHAPS 0-14)
Brief Psychiatric Rating Scale (BPRS, 18-126)
Bech-Rafaelsen Mania Rating Scale (BRMS, 0-44)
Positive and Negative Syndrom Scale (PANSS, 30-210) / 20
39
11
1
41
0
93 / 12
4
7
0
30
0
n.d. / 9
0
7
0
27
0
44 / 4
0
2
0
28
0
47 / 6
10
9
0
22
1
34 / 7
7
8
0
20
1
31
Supplementary table 2. Quality of life and affective state. Presurgical assessment showed moderate, stable depression without suicidal ideation and enhanced anxiety, likely to be related to impaired motor function. During postsurgical course mood markedly improved assessed by depressive scores (BDI, MADRS) including negative symptoms scores (BPRS, PANSS) and anxiety score (BAI). No psychosis (BMRS) and anhedonia (SHAPS) were observed during the observation period of 4 years.
Scores for life satisfaction showed variable scores during postsurgical course in all subscores: general life satisfaction, satisfaction with health, movement disorder and DBS module. At last follow up patient presented an improved life satisfaction in general life satisfaction, satisfaction with health, and with movement disorder compared to presurgical state, except for DBS-module, which showed an improved score at 3 months compared to 3 years postsurgical. Quality of life improved as assessed by mental summary subscore up to four years postsurgery and by physical summery subscore up to 2 years, followed by slight detoriation at the 3- and 4-years visits, n.a. = not assessed
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References (supplementary appendix)
Beck AT, Emery G (1985) Anxiety disorders and phobias: A cognitive perspective.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561-571