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Research ArticleProgramming for Stimulation-Induced Transient NonmotorPsychiatric Symptoms after Bilateral Subthalamic Nucleus DeepBrain Stimulation for Parkinson’s Disease
XiWu,1 Yiqing Qiu,1 Keith Simfukwe,2 Jiali Wang,1 Jianchun Chen,1 and Xiaowu Hu1
1Department of Neurosurgery, Second Military Medical University, Changhai Hospital, No. 168 Changhai Road, Yangpu District,Shanghai, China2Department of Neurosurgery, Changhai Hospital, Second Military Medical University, International College of Exchange,No. 800 Xiangyin Road, Shanghai 200433, China
Correspondence should be addressed to Xiaowu Hu; huxiaowu [email protected]
Received 24 April 2017; Revised 21 June 2017; Accepted 10 July 2017; Published 15 August 2017
Academic Editor: Helio Teive
Copyright © 2017 Xi Wu et al. This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamicnucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine theelectrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motorfunctions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwentprogramming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In thesepatients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients werediagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In onepatient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in onepatient, while five patients recorded eight episodes of hypomania.Therewere no statistical differences between theUPDRS-III underthe final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (𝑝 = 1.000). Conclusion. Theflow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatmentof these symptoms are effective.
1. Introductions
Subthalamic nucleus deep brain stimulation (STN-DBS) isan effective therapy which ameliorates motor manifestationssuffered by patients with idiopathic Parkinson’s disease (PD).The hallmark symptoms in PD patients include tremor,rigidity, and bradykinesia. STN-DBS has been documentedto be well tolerated by PD patients withmarked improvementof motor functions even after over ten-year follow-up [1–3].The limbic system innervates the limbic part of STN andother anatomic surrounding structures that lay in proximity[4]. As a result, the likelihood of accidental tempering ofthese nearby anatomical structures during STN-DBS mayresult in psychiatric symptoms called stimulation-inducedtransient nonmotor psychiatric symptoms (STPS), which are
clinically manifested as depression [5], anxiety [6], apathy[7], explosive-aggressive behavior [8], manic episode [9],mirthful laughter [10], impulse control disorders [11], andso forth. Like other nonmotor functions, in some instances,STPS may have a drastic impact on a patient’s life qualityof life. [12]. It has been noted that the stimulation param-eters which induce STPS are usually higher than normal.Decreasing stimulation intensity on the Implantable PulsarGenerator (IPG) may eliminate STPS. However, patients’motor functions may also be exacerbated. Changhai HospitalNeurosurgery Department conducts more than 160DBSimplantation surgeries every year. Since December 2014,the therapeutic center for Parkinson’s disease in ChanghaiHospital, Shanghai, China, has designed and implemented(1) an algorithm that identifies specific electrode contacts
HindawiParkinson’s DiseaseVolume 2017, Article ID 2615619, 14 pageshttps://doi.org/10.1155/2017/2615619
2 Parkinson’s Disease
Figure 1: Merging SWI sequence with postoperation CT to deter-mine the electrode position.
that induce STPS (2) a programming protocol to eliminateSTPS. This study aim is to assess the effectiveness of thesealgorithms.
2. Materials and Methods
2.1. Patients. After acquiring approval from the Ethics Com-mittee of Changhai Hospital, we retrospectively analyzed allpatients with idiopathic Parkinson’s disease who receivedclinical programming of implanted bilateral STN-DBS in theDBS programming clinic of Changhai Hospital, Shanghai,China, from January 1, 2015, to December 31, 2015. Patientswho are being initiated on DBS, as well as those receivingfollow-up programming sessions due to various reasons afterachieving optimal stimulation parameters, were included inthe present study. The UK PD Brain Bank diagnostic criteriawere adopted for the diagnosis of idiopathic Parkinson’sdisease.
2.2. Mapping the Active Contact. If the active contact is notwithin the STN, the programming protocol may be lesseffective. Therefore we reviewed intraoperative MRI of allthe patients with Leksell G frame and indicator to confirmthe electrode location. The Medtronic S7 Neuro NavigationSystem (Medtronic Navigation, Louisville, USA) was used tomerge preoperative 3.0T-MRI images with postoperative CTimages.TheCT scan imageswere calibrated at 1mm thicknessand without pneumocranium (Figure 1). It was essential thatthe active contact center is placed within the boundaries ofthe STN. Patients with the active contact center outside STNboundary were excluded from this study.
2.3. Motor Assessment. Patient’s motor function was gradedusing the Unified Parkinson’s Disease Rating Scale Part III(UPDRS-III, 1998 edition). All patients included in this
study were assessed preoperatively, postoperatively and then,finally, before and after the occurrence of STPS. All clinicianswho administered the Unified Parkinson’s Disease RatingScale in this study are board-certified with the InternationalParkinson and Movement Disorder Society.
2.4. Cognitive and Psychiatric Assessment. All patients withSTPS were enrolled in this study. Patients that had any mildpsychiatric episodes that occurredmore than twice as a resultof programming (increasing) the electrode power parametersat home by oneself or caregivers were enrolled in this study.Episodes of acute psychiatric symptoms during or after theclinic programming procedures were also enlisted. Patientswith psychiatric symptoms similar to the preoperative onesor had changed medication dose in less than one month wereexcluded. This was because it would be difficult to confirmwhether the symptoms were induced by electric stimulationor not. So, only new postoperative psychiatric symptomswere regarded as suspicious STPS. The litmus test for STPSidentification was defined by (1) psychiatric symptoms ofpatients which improved after decreasing stimulation inten-sity in 30 minutes; however, this could also confirm that theSTPS was induced by stimulation because it occurred at thetime when stimulation intensity was increased to improvethe patient’s motor functions, (2) patients who must have nosimilar history of psychiatric symptoms and upon clinicalprogramming have shownmarked improvementwithin threemonths without any change in the medication, and (3)identification of causative STPS active contact.
Cognitive and depressive symptoms were evaluated pre-operatively and graded using Unified Parkinson’s DiseaseRating Scale Parts I and II (UPDRS-I and UPDRS-II), theMini-Mental State Examination (MMSE), and the 17-itemHamilton Depression Scale (HAM-D-17). Mania type STPSwas graded using the Young Mania Rating Scale (YMRS)[13].TheYMRSwas calculated using patient collateral historyfrom caregivers and direct observation by the physicians.Patients with STPS while being initiated on IPG wererecorded using preoperative evaluation results only.
2.5. Assessment of STPS and Recording of Stimulation Param-eters. Patient’s collateral history regarding unusual psychi-atric symptoms recorded in programming sessions wasreviewed. Stimulus parameters (active, stimulating contacts,stimulating pattern, voltage/current, pulse width, and fre-quency) were recorded following the occurrence of STPS.Changes and the final status of stimulation parameters inprogramming sessionswere also recorded. Electrode contactsinducing STPS and programming protocols were determinedaccording to previously established flow diagrams (Figures2 and 3). The disappearance of STPS was determined by norelapse of similar psychiatric symptoms for three monthsafter programming.
2.6. Statistical Analysis. Paired-sample 𝑡-test was used toexamine for changes of variables in UPDRS-III duringclinical evaluation. 𝑝 < 0.05 was considered statisticallysignificant.
Parkinson’s Disease 3
Suspected episode of STPS
Symptoms inremission
Acute symptomsPresent
Bilateral adjustment in the last programming
Unilateral adjustmentin the last programming
Bilateral adjustment in the last programming
Unilaterally adjustment in last programming
Adjust single contact Adjust multiple contacts
Con�rm responsible contact Turn o� lower contacts
STPSs disappear?
Do STPSs disappear inassessment when all le�contacts switched to OFF?
NoYes
Yes, le�No, right
STPSs remain with allcontacts turned o� Diagnosis error of STPS
Increased single contactstimulation power last time
Increased multiple contactsstimulation power last time
10 min
Teach patient waiting forsimilar STPS for 2 weeks
Turn voltage to 0 V bypatient or caregiver, thenSTPS relieved in 15 min?
Had other suspectedactivated contacts?
Do STPSs appear?
Con�rm responsible contact
No Yes
Yes
No
Retain the lowest contacts and recoverthe other contacts parameters
Test for single contact
Test the other contacts
Resumption of right electrode parameters and follow-up for 2 weeks
Relapse, le� sideNo relapse, mean right side
Yes
No
DescriptionCon�rmation of electrode positionCon�rmation of causative contact
Figure 2: Flow diagram to determine electrode contacts inducing STPS.
3. Results
3.1. Baseline Data. There were three groups of patientsenrolled in this study: (1) the first group is comprised of 145patients undergoing DBS initiation 1 month postoperativelyfor optimal programming parameter; (2) the second grouphad 231 patients who underwent DBS less than one yearpostoperatively; (3) finally, the third group had 166 patientswho underwent DBS more than one year postoperatively.There were a total number of 1142 episodes of clinicalprogramming for the purpose of adjusting the stimulationparameters in the second and third groups. There were 20episodes of STPS that occurred in 11 patients (6 females and5 males). The mean age at the time of DBS surgery was63.45 ± 8.27 years. Themean duration between identificationof Parkinsonian symptoms and DBS surgery was 11.91 ±3.33 years. Cognitive functional impairment was excluded inall patients. Only six patients received antidepressant drugsbefore and after surgery, while the rest of the patients had noobvious depression symptoms. Preoperatively, patients weregiven an average Levodopa Equivalent Daily Dose (LEDD) of942.5 ± 232.7mg. Postoperatively, before the STPS occurred,the LEDD was reduced to 404.5 ± 353.3mg. By the time pro-gramming eliminated STPS at 3 months after programming,
the LEDD had further reduced to 284.5 ± 187.8mg.The UPDRS-III improvement rate between postoperative(med-off time) status and preoperative (med-off time) statuswas 35.14∼72.34% at 3 months after programming. When wecompared the baseline data of STPS + patients versus STPS −patients to characterize patients inherent risk factors forSTPS, no significant statistical difference was found betweengroups (see Table 1).
3.2. STPS Occurrence. During the programming, 20 episodesof STPS occurred in 11 patients. These psychiatric symptomsconsisted of four (04) episodes of crying in two (02) patients,four (04) episodes of inexplicable euphoria or mirthfullaughter in two (02) patients, two (02) episodes of spatialdisorientation in one patient, two (02) episodes of hallucina-tion in one patient, and eight (08) episodes of hypomania infive (05) patients. In five (05) patients, STPS occurred duringtitration adjustment for optimal programming parameterin the first year after devices were implanted, while two(02) patients showed psychiatric symptoms two days afterbeing started on IPG and discharged from the hospital.For patients who had implanted devices for more thanone year, three (03) developed STPS during programmingsessions. Manifestations of patients during STPS episodes
4 Parkinson’s Disease
Maintain the voltage andswitch to bipolar electrodes
Reduce voltage and increasepulse width from (A)
Decline voltage and frequency and increase pulse width from (D)
Decrease voltage, frequency, andinterleaving of dorsal contacts
Change to dorsal contacts from (A)
Reduce voltage by 0.3 V–0.5 V until SITNPS disappears
Monopolar Bipolar Double polarInterleaving
Motor symptoms poorlyimproved
STPSs relapse
STPSs relapse ormotor symptomspoorly improved
STPSs relapse
Motor symptoms poorlyimproved
Motor symptomspoorly improved orSTPS remained
(A)
(B)
(C)
(D)
(E)
(G)
(F)
Figure 3: Programming protocol flow diagram (After determining STPS causative active contacts with Figure 2, (A) record the initialparameters and programming according to the stimulation mode; (D) recover the initial parameters and reduce voltage 0.3 V–0.5V andincrease pulse width by 10–20 𝜇s; (E) if STPS relapsed, then reduce voltage 0.1–0.3 V and reduce frequency 10–30Hz, increase pulse width10–20𝜇s, and keep the total electrical energy delivered (TEED) equal to the counterpart of (D), TEED = voltage2 × frequency × pulsewidth/impedance; (F) decrease frequency to 125Hz and decrease voltage 0.3–0.5 V, and keep the TEED equal or slightly higher to thecounterpart of (D) or (E); activate the other dorsal contact with interleaving mode.).
were described in Table 2.The stimulation parameters beforethe onset of STPS were listed in Table 3.
3.3. Programming of STPS and Motor Functions. Followingthe adjustment of stimulation parameters (Table 3), tenpatients maintained the improvement of motor functionswith psychiatric symptoms eliminated.The adjustments werebased on the algorithms as follows: (1) the stimulation voltagedecreased while the pulse width increased in 2 patients(numbers 1 and 11); (2) the voltage was maintained whileswitching to bipolar stimulation in 2 patients (numbers 2and 7); (3) voltage and frequency were decreased with pulsewidth increased in 1 patient (number 9); (4) voltage andfrequency were decreased while switching to interleavingstimulation in 3 patients (numbers 3, 4, and 10); (5) theactivation contacts were replaced with dorsal ones in 2patients (numbers 5 and 8). One patient (number 6), aftermultiple programming sessions, developed concurrentmotorand nonmotor functions, and UPDRS-III score increasedby 2 points under the final stimulation parameters by herchoice (see details of the programming duration in Table 4).There were no statistical differences between the UPDRS-IIIunder the final stimulation parameter (without STPSs) andoptimum UPDRS-III under the STPSs (26.45 ± 10.59 versus26.45 ± 10.17, 𝑝 = 1.000).
4. Discussion
4.1. The Clinical Value of Programming Algorithms for STPS.Since the application of STN-DBS in the treatment of PDpatients, there have been sporadic reports [10] noting STPSs,as one of the side effects. The development of these pro-gramming algorithms is aiming to reduce the ambiguityin the management of STPS. The ambiguity was on thepredisposition of the following. (1) In earlier studies, STPSwas implicated with stimulation of the medial and inferiorpart (limbic part) of STN. However, recent studies show theiractive contacts located in the dorsolateral (sensorimotor) areaof STN [14] which also induces STPS. Because of this reason,the limbic and sensorimotor regions of the STN overlapwere greater than what has been previously reported [15].In this study, we also found that the active contacts whichinduced STPS were located at a medial and inferior partof the STN in seven (07) patients. In the other four (04)patients, the active contacts were located in the lateral partof STN which also induced STPS. This is similar to whatwas reported by Abulseoud and colleagues [14]. For thisreason, we concluded that the side effects of STPS are difficultto avoid by just implanting contacts into dorsolateral STN.(2) Secondly, under the routine stimulation parameter, thespherical radius of active volume (without contacts volume)
Parkinson’s Disease 5
Table1
(a)Ba
selin
eclin
icaldataof
patie
ntsw
hodevelopedST
PS.
Age
Gender
Duration
(year)
MMSE
HAMD
(𝛼)
LEDDpre-op
(mg)
LEED
STPS
Emerged
LEDD3m
post-
STPS
(mg)
UPD
RSI
UPD
RSII
UPD
RS-III
UPD
RSIV
Pre-op
med-off
Pre-op
med-on
PD1
61M
1729
19(14
)1200
1200
550
817
4713
3PD
252
M14
2910
900
125
125
418
4115
6PD
359
F8
3021
(16)
768
325
300
724
5326
9PD
474
M7
2610
563
175
175
631
3724
11PD
561
M8
2917
(10)
825
825
280
511
4315
10PD
658
M11
2630
(17)
1100
325
325
1018
7542
4PD
752
F15
2711
963
7575
213
7034
3PD
875
F13
2716
1287
300
200
420
8137
8PD
972
F10
288
787
250
250
413
2716
4PD
1064
F13
2624
(13)
750
150
150
516
5128
7PD
1170
F15
2730
(16)
1225
700
700
922
6331
10𝛼:post-a
ntidepressiontre
atment;LE
DD:L
evod
opaE
quivalentD
ailyDose.
(b)Com
pare
theb
aselined
atao
fSTP
Spo
sitiveV
ersusS
TPSnegativ
epatients.
STPS
+ST
PS−
𝑝value
Patie
nt11
443𝛽
Age
63.45±8.28
62.05±7.7
80.555
Dise
ased
urationto
DBS
11.91±
3.33
9.95±4.03
0.112
LEDDpre-op
(mg)
942.55±232.67
836.32±393.79
0.374
UPD
RS-IIImed-offpre-op
53.45±16.94
52.46±14.24
0.819
UPD
RS-IIImed-onpre-op
25.55±9.9
125.80±11.14
0.940
MMSE
27.64±1.4
327.07±2.57
0.463
HAMDbefore
receivingantid
epressantd
rug
17.82±7.8
520.71±
6.21
0.130
𝛽:443
patientsincludedthreeg
roup
s:145p
atientsinitiatedtheIPG
and99
ofthem
achieved
theo
ptim
alprogrammingp
aram
etersb
eforethe
study
was
finish
ed;the
99patie
ntsa
ndother132
patie
ntwho
achieved
theo
ptim
alprogrammingparametersreceivedST
N-D
BSforlessthanon
eyear.166patie
ntsh
adreceived
STN-D
BSform
orethanon
eyear:145+132+166=44
3.
6 Parkinson’s Disease
Table2:Clinicalmanifestations
ofST
PS.
Num
ber
Descriptio
nof
episo
deRe
latio
nshipwith
medication
Duration
Times
Chiefcom
plaintsa
ndsymptom
sYM
RSIntervalbetween
episo
deand
operation
Timeo
foccurrence
(1)
1Inexplicableeuph
oria(sense
offlo
ating)
22Po
stoperativ
e1mon
th(new
lyactiv
ated)
Day
1afte
rhospital
discharge
Med-on1.5
h2h
2Inexplicableeuph
oria(sense
offlo
ating)
Day
2aft
erho
spita
ldischarge
Med-on1h
2.5h
(2)
1Wail
none
Posto
perativ
e18
mon
ths
During
programming
MED
+ON
20min
(3)
1Hallucinatio
n(cloud
-like
light
andshadow
)no
nePo
stoperativ
e2mon
ths
Firstn
ight
after
hospita
ldisc
harge
Med-on
Abou
t20m
in
2Hallucinatio
n(cloud
-like
light
andshadow
)Second
morning
after
programming
Med-on
30min
(4)
1Hypom
ania(hardto
restr
ainanger)
30Po
stoperativ
e17
mon
ths
During
programming
Med-off
10min
until
adjustmento
fparameter
2Hypom
ania(sense
ofanger)
28During
programming
Med-off
10min
until
adjustmento
fparameter
(5)
1Wail(indu
cedby
ordinary
conversatio
n)
none
Posto
perativ
e1mon
th(new
lyactiv
ated)
During
programming
Med-off
5min
until
adjustmento
fparameter
2Wail(indu
cedby
ordinary
conversatio
n)During
programming
Med-off
7min
3Wail(indu
cedby
talkingabou
tthe
past)
During
programming
Med-on
5min
(6)
1Hypom
ania(lo
singtempertowife)
33
Posto
perativ
e26
mon
ths
Atho
me,aft
erprogramming
Med-on
Improved
after
10min
2Hypom
ania(kicking
roadsid
ecars)
Atho
me,aft
erprogramming
Med-on
2min,improved
1min
after
deactiv
ation
(7)
1Inexplicableeuph
oria(la
ughing
foolish
ly)
20Po
stoperativ
e3mon
ths(du
ring
programming)
During
programming
1haft
erintake
10h
2Inexplicableeuph
oria(la
ughing
foolish
ly)
During
programming
1.5haft
erintake
3min
(8)
1Hypom
ania(lo
sttempera
ndsm
ashedob
jects)
34Po
stoperativ
e3mon
ths(du
ring
programming)
The2
nddayaft
erho
spita
ldisc
harge
Med-on
2h
2Hypom
ania(flight
ofideasa
ndfid
getin
g)Th
e2nd
dayaft
ergetting
home
Med-on
2h
(9)
1Hypom
ania(emotionaland
quarrelin
g)34
Posto
perativ
e14
mon
ths
Day
6aft
erho
spita
ldischarge;20
min
after
raising
the
voltage
of0.5V
with
programming
bypatie
nts
Med-on1.5
h
1.5h.Family
mem
bers
resto
redthes
timulation
parameter
originallysetb
ydo
ctors
Parkinson’s Disease 7
Table2:Con
tinued.
Num
ber
Descriptio
nof
episo
deRe
latio
nshipwith
medication
Duration
Times
Chiefcom
plaintsa
ndsymptom
sYM
RSIntervalbetween
episo
deand
operation
Timeo
foccurrence
(10)
1Ab
norm
alsenseo
fspatia
lorie
ntation(unaware
ofhislocationwhenou
tofclin
ic)
none
Posto
perativ
e3.5
mon
ths(du
ring
programming)
During
programming
Med-off
10min,returnedclinicfor
readjustmento
fparam
eters
2Ab
norm
alsenseo
fspatia
lorie
ntation
During
programming
Med-off
15min,improved
2min
after
parameter
adjustment
(11)
1Hypom
ania(sho
utingandfid
getin
g)29
Posto
perativ
e2.5
mon
ths(du
ring
programming)
Inthec
aron
his
way
homea
fter
programming
Med-on
1.5h,im
proved
after
readjustmento
fparam
eters
inthec
linic
8 Parkinson’s Disease
Table3:Th
estim
ulationparametersa
ndST
PS.
Num
ber
ofPD
Patie
nts
Status
STPS
times
Chiefcom
plaints
andsymptom
sof
STPS
Stim
ulation
patte
rnCV
/CC
Intensity
(V/m
A)
Pulse
width
(𝜇s)
Frequency
(Hz)
Left/rig
htCa
thod
eAno
deIPG
Electro
deAc
tivec
ontact
locatio
nUPD
RS-IIIscore
(med
off/IP
G-on)
(1)
Pre-ST
PSIPG-off
Activ
aRC
3389
MedialSTN
STPS
1Inexplicable
euph
oria
Mon
opolar
CV2.5
60160
Left
1Ca
seNon
e∗
STPS
2Inexplicable
euph
oria
Mon
opolar
CV2.2
60160
Left
1Ca
se14
Final
Mon
opolar
CV1.9
70160
Left
1Ca
se14
(2)
Pre-ST
PSMon
opolar
CV2.3
80140
Left
1Ca
se
Activ
aRC
3389
Medialp
arto
fST
NMon
opolar
CV2.5
90140
Right
9Ca
seST
PS1
Wail
Mon
opolar
CV2.5
90140
Left
1Ca
se13
Final
Bipo
lar
CV2.6
90140
Left
12
13
(3)
Pre-ST
PSMon
opolar
CV2.5
60150
Right
9Ca
se
Activ
aRC
3389
MedialInferior
partof
STN
Mon
opolar
2.3
60150
Left
2Ca
seST
PS1
Hallucinatio
nMon
opolar
CV2.9
70150
Right
9Ca
se25
STPS
2Hallucinatio
nMon
opolar
2.6
90130
Right
9Ca
se23
Final
Interle
aving
CV2.5
90125
Right
2Ca
se23
1.870
125
3
(4)
Pre-ST
PSMon
opolar
CV2.3
100
90Left
1Ca
se
Activ
aRC
3389
Inferio
rparto
fST
N/sub
stantia
nigra
Mon
opolar
CV2.5
11090
Right
10Ca
seST
PS1
Hypom
ania
Dou
blep
olar
CV2.4
100
90Left
0,1
Case
25ST
PS2
Hypom
ania
Dou
blep
olar
CV2.2
110
85Left
0,1
Case
25
Final
Interle
aving
CV2.0
100
90Left
0Ca
se25
2.3
100
901
(5)
Pre-ST
PSIPGoff
Activ
aPC
3389
Lateralp
arto
fST
N/C
lose
toZo
naincerta
STPS
1Wail
Mon
opolar
CC1.9
60140
Right
10Ca
seNon
e∗
STPS
2Wail
Mon
opolar
CC1.7
60130
Right
10Ca
se13
STPS
3Wail
Bipo
lar
CC1.8
60130
Right
1011
13Final
Mon
opolar
CC1.9
60130
Right
11Ca
se13
(6)
Pre-ST
PSDou
ble-po
lar
CV2.5
60160
Left
0,1
Case
Activ
aRC
3389
Inferio
rparto
fST
N/C
lose
tosubstantianigra
Mon
opolar
CV2.7
70160
Right
9Ca
seST
PS1
Hypom
ania
Dou
blep
olar
CV2.8
60160
Left
0,1
Case
40
STPS
2Hypom
ania
Interle
aving
CV2.5
80125
Left
0Ca
se39
2.8
80125
1Ca
se
Final
Interle
aving
CV2.5
70125
Left
0Ca
se41
2.7
80125
1,2Ca
se
(7)
Pre-ST
PSMon
opolar
CC2.1
60145
Left
3Ca
se
Activ
aRC
3389
Lateralp
arto
fST
N/C
lose
toInternalcapsule
Mon
opolar
CC2.0
70145
Right
10Ca
se
STPS
1Inexplicable
euph
oria
Mon
opolar
CC2.1
60145
Left
3Ca
se40
STPS
2Inexplicable
euph
oria
Mon
opolar
CC1.9
70145
Left
3Ca
se38
Final
Bipo
lar
CV2.3
70145
Left
32
38
Parkinson’s Disease 9
Table3:Con
tinued.
Num
ber
ofPD
Patie
nts
Status
STPS
times
Chiefcom
plaints
andsymptom
sof
STPS
Stim
ulation
patte
rnCV
/CC
Intensity
(V/m
A)
Pulse
width
(𝜇s)
Frequency
(Hz)
Left/rig
htCa
thod
eAno
deIPG
Electro
deAc
tivec
ontact
locatio
nUPD
RS-IIIscore
(med
off/IP
G-on)
(8)
Pre-ST
PSMon
opolar
CV2.6
60150
Left
1Ca
se
Activ
aRC
3389
Medialp
arto
fST
N
Mon
opolar
CV2.5
60150
Right
10Ca
seST
PS1
Hypom
ania
Mon
opolar
CV3.1
60150
Left
1Ca
se40
STPS
2Hypom
ania
Mon
opolar
CV2.8
70145
Left
1Ca
se40
Final
Mon
opolar
CV3
60140
Left
2case
40
(9)
Pre-ST
PSMon
opolar
CV2.7
90160
Right
9Ca
se
Activ
aRC
3389
Lateralp
arto
fST
NDou
ble-po
lar
CV2.5
80160
Left
2,3
Case
STPS
1Hypom
ania
Mon
opolar
CV3.2
90160
Right
9Ca
se25
Final
Mon
opolar
CV2.9
110130
Right
9Ca
se24
(10)
Pre-ST
PSMon
opolar
CC2.0
60160
Right
9Ca
se
Activ
aPC
3389
Medialp
arto
fST
N
Mon
opolar
CC2.2
60160
Left
2Ca
se
STPS
1Ab
norm
alspatial
orientation
Mon
opolar
CC2.2
60160
Right
9Ca
se26
STPS
2Ab
norm
alspatial
orientation
Mon
opolar
CC2.0
70140
Right
9Ca
se25
Final
Interle
aving
CV2.8
60125
Right
9Ca
se25
2.1
60125
10Ca
se
(11)
Pre-ST
PSMon
opolar
CV2.8
70135
Left
2Ca
se
Activ
aRC
3389
Lateralp
arto
fST
NMon
opolar
CV2.5
60135
Right
10Ca
seST
PS1
Hypom
ania
Mon
opolar
CV3.0
70135
Left
2Ca
se34
Final
Mon
opolar
CV2.7
80135
Left
2Ca
se34
CV,con
stantvoltage;C
C,constant
current.∗Th
epatientsw
ithno
UPD
RS-IIIscore(med-off/IPG-on)
becausetheywereinthefi
rstp
rogram
mingandhave
notb
eenevaluatedwith
UPD
RS-IIIscorey
et.
10 Parkinson’s Disease
Table4:Programmingprocedureo
fpatient
number6
.
Patte
rnVo
ltage
(V)
Pulse
width
(𝜇s)
Frequency
(Hz)
Cathod
eAno
deUPD
RS-IIIscore
(med-off/IPG-on)
Chiefcom
plaints
Pre-programming
Dou
blep
olar
2.5
60160
0,1
Case
41Spastic
pain
inther
ight
shou
lder
(1)
Dou
blep
olar
2.8
80160
0,1
Case
40ST
PSoccurred
(2)
Interle
aving
2.5
80125
0Ca
se39
STPS
occurred
with
hat-likec
onstr
ictio
nsurrou
ndingtheh
ead
2.8
80125
1Ca
se
(3)
Interle
aving
2.5
70125
0Ca
se40
Rigidityof
neck
andpo
sterio
rextensio
n2.8
90125
1Ca
se
(4)
Interle
aving
2.5
70125
0Ca
se39
Dizzinessandpalpitatio
n3.1
80125
1Ca
se
(5)
Dou
blep
olar
2.5
70130
0,1
Case
40Fidgeting,feellik
eprelim
inaryappearance
ofST
PS
(6)
Interle
aving
2.5
70125
0Ca
se40
Dizzy
andpalpitatio
n2.7
100
125
1Ca
se
(7)
Interle
aving
2.5
70125
0Ca
se42
Rigidityof
neck
andpo
sterio
rextensio
nwith
pain
inther
ight
shou
lder.
2.8
80125
12
(8)∗
Interle
aving
2.5
70125
0Ca
se41
Pain
inshou
ldersimproved,w
ithno
newly
developedsymptom
s2.7
80125
1,2Ca
se
(9)
Interle
aving
2.5
70125
0Ca
se41
Dizziness
2.8
80125
1,2Ca
se∗Th
epatient
chosethe
8thprogrammingparameters.
Parkinson’s Disease 11
could reach to 3mm. As a result, the limbic part of STNcould easily be affected and cause STPS. (3) Thirdly, evenin the most experienced PD treatment center could notguarantee that both anticipated contacts location and curativestimulation effect could be satisfied. Meanwhile, STPS couldbe easily induced when increasing stimulation intensity ortesting side effects.
China has the largest number of patients with PD in theworld. In recent years, there have been more than 100 centerswhich carry out STN-DBS surgery for the treatment of PD.Asa result, there is a strong likelihood of an increasing numberof PD patients suffering STPS after STN-DBS programming.It is therefore very important to rapidly diagnose, locatecontacts, and program parameters to eliminate STPS. Itis also paramount to maintain the PD patient’s optimalmotor function according to algorithms set by programmingdoctors at different levels.
4.2. Confirmation of STPS and the Impact Factors. Psychiatricdisorders are one of the symptomsmanifested in PD patients.However, antiparkinsonism medications also manifest simi-lar symptoms as drug side effects. Levodopa and dopaminer-gic drugs could induce dopamine dysregulation syndrome,hallucinations and psychosis, mania and hypomania, andimpulse control disorders, which were similar to STPS [16].The treatment of psychiatric symptoms induced by the abovedrugs is in the reduction of medication in most times. STPSis known to manifest similarly. Therefore the diagnosis ofpsychiatric symptoms induced by drug side effects or PDshould not bemisinterpreted for STPS.The diagnosis of STPSshould only be made upon confirmation.
Patients in our study had neither any preexisting psychi-atric symptoms nor their PDmedication altered for than onemonth. Although preoperative LEDD given to our patientson average was more than the reported average dose beforeDBS surgery in previous studies [17, 18], the subsequent doseswould reducemore than 50% similar to that reported by Jiangand colleagues [17]. Levodopa withdrawal symptoms mainlyinclude apathy and depression. In our study, all 11 patients hadno symptoms of apathy and depression. Moreover in the firstthree-month follow-up after STPS programming, except forthe two patients who had STPS at IPG initiation, there was nochange in the LEDD in the other patients (Table 1).We, there-fore, deduced that the antiparkinsonismmedication is not themain factor inducing psychiatric symptoms.Otherwise, somepsychiatric symptoms may have reoccurred within the first 3months of follow-up.
To avoid drugs side effect interference during DBS effectevaluation, all the patients were programming in the state of“off time.” Patients were given daily doses of anti-Parkinson’sdisease drugs after the final stimulation parameters wereset. To achieve the satisfactory therapeutic effects, the motorcomplications were evaluated during “on time” state. How-ever, the interesting point is that 70% (14/20) STPS occurredin “on time” state or over 1 hour after taking medications(though some patients had not felt medicine effect already);see Table 2.Whether medications for PDwork with electricalstimulation to cause psychiatric symptoms or not needs fur-ther study.We excluded the effect of PD drugs bymaintaining
the same dosage that was given on the first occurrence ofSTPS. So we believe the electrical stimulation should be themain factor of psychiatric symptoms.
To improve the diagnosis of STPS, we developed thealgorithm (Figure 2). The causative active contact of patientswith acute symptoms of STPS could be easily identifiedusing the flow chart. However, the causative active contactin patients with transient STPS symptoms was more difficultto identify. In the process of locating suspicious contacts insuch patients, we do not recommend increasing stimulationintensity to induce STPS to identify contacts. The reason isthat (1), theoretically, increasing stimulation intensity of anycontact to a certain threshold, the volume of tissue activated(VTA) may affect limbic part of STN and induce STPS. So itmaymislead the doctor to regard the contacts which were notthe initial responsible contacts. The doctor may even locatewrong responsible electrodes and contacts. (2) If there aremultiple active contacts (double polar, interleaving mode) onone side of the electrode, the adjacent contacts have a higherchance to induce STPS (although the ventral contacts arewith a higher chance). If randomly increasing stimulationintensity of random contacts to induce STPS, it can alsolead to wrong contact. (3) Intentionally induced STPS mightcause patients extra distress, leading them to distrust doctors,increased complaints, and decreased satisfaction. Therefore,we recommend the utilization of the algorithm (Figure 2) tolocate the contacts carefully and accurately. In our study, theactive contacts which induced STPS were identified by usingan algorithm (Figure 2) and eliminated by programming inall the 11 patients.
The clinical significance incidence rate of STPS whichnecessitated programming was about 2%. This was signifi-cantly lower as compared to 28.6% in previous studies [14].This difference may be attributed to the stimulation intensityused and the exclusion criteria we used to enroll patients withSTPS symptoms in this study. In this study, the stimulatingvoltage was rarely more than 3.0V. However, the stimulatingvoltage did not exceed 3.3 V.
We noted that time interval for the occurrence STPS fellwithin 48 hours after new settings of stimulation parameters.Therefore, the psychiatric and psychological status of patientsshould be thoroughly assessed in MED-ON/STIM-ON aftereach programming session before patients were discharged.It is also necessary to instruct the family to timely identifythe occurrence of STPS, since some symptoms may not berecognized by patients themselves [19].
4.3. Principles of STPS Programming. We observed that STPSis likely to develop when programming clinicians increasethe voltage or pulse width of the active contact. The increasein active contact voltage or pulse width gives patients abrief false sense of relief masked by improvement in motorfunctions. Even though the improvement of motor functionsare most often minor (1 or 2 point differences in UPDRS-III), STPS set in as residual effects of the increase in voltage.Patients usually find themselves in a quagmire on whetherto maintain improved motor functions or settle for removalof STPS and have less appealing motor functions. However,few reports were mentioning how to maintain the optimal
12 Parkinson’s Disease
improvement for motor functions while avoiding STPS at thesame time.
We conducted a literature review using PubMed databaseof earlier authors who encountered and managed STPSwhile maintaining optimal motor functions. We designed aprogramming procedure andprotocol to determine the activecontacts that induce STPS to rapidly alleviate patients’ psychi-atric symptoms and maintain improved motor functions.
Previous reports [20] suggest that STPS was associatedwith high level of voltage. This suggests that the VTA mightimpact the limbic neuronal networks that induce STPS.They further reported that various programming methodsdecrease or change the VTA enabling eliminating STPS.These methods include (1) reducing voltage [20], (2) switch-ing to bipolar stimulation [19], and (3) changing dorsal activecontacts [9, 21, 22].
Although there are many ways to improve STPS throughprogramming, the order of choice must not be random butwith precise principles and in chronological order (Figure 3).These principles include that (1) the solutions for eliminatingSTPS must be rapid; (2) simple and replicable; (3) and withminimal or no STPS reoccurrence and (4) must preserveoptimal motor functions.
There are six methods to adjust the stimulation param-eter: (1) bipolar stimulation, (2) reducing voltage by 0.3 V–0.5 V until SITNPS disappears; (3) decreasing of voltageand increasing the pulse width; (4) declining voltage andfrequency and increasing pulse width; (5) interleaving oforiginal and dorsal contacts; (6) changing the active contactsto dorsal the position.
4.3.1. Bipolar Stimulation. The first option is bipolar stimu-lation. We choose to select bipolar stimulation to easily setstimulation parameters and quickly narrow the sphere VTA(Figure 3). This could promote STPS regression and reducerecurrence. However, due to the rapid narrowing of VTA, itoften leads to the aggravation of motor functions.
4.3.2. Reducing Voltage. We reduced the voltage on the basisof initial stimulation parameter (with STPS).This adjustmentcan also quickly reduce the VTA and intensity of the activa-tion domain.
4.3.3. Decreasing of Voltage and Increasing the Pulse Width.The adjustment of programming parameters mentionedabove may reduce activation domain [23] while in the mean-time declining the stimulating intensity of motor functions-related neural pathways [24].Therefore a slight increase in thepulse width tomaintain stimulation intensity in the narrowedVTA might be needed when the voltage is decreased. Someinexperienced programming physicians may conceive that itis hard tomodulate pulse width appropriately. It will be easierto operate according to the formula of total electrical energydelivered (TEED) to calculate how to increase the pulse widthaccording to the voltage reduced (new TEED should be notmore than the original one with STPS).
4.3.4. Declining Voltage and Frequency and Increasing PulseWidth. If necessary, we can even adjust the frequency
(+5–10Hz) to fit the change of the voltage and pulse width,to achieve the appropriate stimulation intensity to eliminateSTPS while maintaining the improvement of motor func-tions. In addition to reducing the stimulation frequency toreduce intensity, interleaving technology could be used whenadjusting the voltage.
4.3.5. Interleaving of Original and Dorsal Contacts. Theadjustment of the pulse width is critical in improving patient’soptimal movement symptom after the frequency has reducedto 125Hz. In the case where the active contact responsiblefor inducing STPS was ventrally positioned, stimulationparameters remain unaltered. Subsequently, the dorsallylocated contacts are activated into interleaving stimulationmode.This adjustment has proven tomaintain optimalmotorfunction.
4.3.6. Changing the Active Contacts to Dorsal the Position.In isolated patients, motor functions reacted better to stim-ulation frequency than the later adjustment. As reported,the contacts located anterior, medial, and inferior to STNwere easier to precipitate STPS [14]; thus if using theabove-mentioned scheme cannot eliminate STPS and achieveoptimal improvement of motor functions at the same time,we change the active contact to more dorsal position toacquire a larger range in the adjustment of stimulationparameters. If the inactive contacts were suspended for along time, curative and side effects might change fromprevious stimulation record and need retitration which istime-consuming. Also, after the inactivated contacts havebeen activated, the contact impedance may change with timecausing instability of symptom control among patients [25].We recommend that the interleaving mode generates twoisolated VTA: the ventral and dorsal contact. The ventralcontactmaintains the previous stimulation parameters beforethe occurrence of STPS. We activate the dorsal contact bygradually increasing the voltage and pulse width to archiveoptimal motor function [26]. In contrast to the COMPAREtrial [27], we have put in consideration preserving patient’smotor function while eliminating STPS. Therefore the use ofinterleaving stimulation was our priority than changing theactive contact to dorsal one.
4.4. Patient Follow-Up. The impedance of the active contactsreduces over time [25]. Therefore, after STPS programming,patients needed to be followed up for a period to ensureno appearance of similar psychiatric symptoms. STPS wasconsidered eliminated after clinical programming at three(03) months. In the event there was a need to adjust theintensity of stimulation upwards, increasing the width ofpulse was given priority. This is because the expansion of theactivated domain was not as significant as that of the voltage[28].
4.5. Limitations. The limitations of the study are inadequatesample size and limited categories of STPS. Additionally, theflow diagrams adopted in this study are limited to MedtronicActiva PC and RC models. This was a single center study.
Parkinson’s Disease 13
5. Conclusion
The stimulation contacts in STPS could be determined withuse of flowdiagram.Appropriate programming could removeSTPS while maintaining optimal improvement of motorfunctions for most patients.
Additional Points
Recommendations. The flow diagrams for patients with othermodels of IPG should be adjusted accordingly. A meta-analysis could increase the sample size and attain statisticalsignificance.
Disclosure
Thisworkwas presented as a poster at the 2017 ChineseMedi-cal Association of Nerve Regulation Professional CommitteeAnnual Meeting and the 8th Session of the Chinese NerveRegulation Conference. Xi Wu and Yiqing Qiu are co-firstauthors.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Acknowledgments
This work was supported by the National Key Research andDevelopment Program of China (2016YFC0105900).
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