Moving forward in childhood-onset movement disorders
Eggink, Hendriekje
DOI:
10.33612/diss.94395271
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Eggink, H. (2019). Moving forward in childhood-onset movement disorders: a multidisciplinary approach to
diagnosis and care. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.94395271
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
STIMULATION IN DYSTONIA: A SYSTEMATIC
REVIEW
HENDRIEKJE EGGINK
STANISLAW SZLUFIK
MARAIKE A. COENEN
MARTJE E. VAN EGMOND
ELENA MORO
MARINA A.J. TIJSSEN
ABSTRACT
Introduction: Deep brain stimulation (DBS) has emerged as an effective treatment in medically intractable dystonia, with the globus pallidus internus (GPi) being most frequently targeted. Non-motor symptoms, including pain and psychiatric, cognitive and sleep disturbances, are increasingly recognized as important determinants of disease burden in dystonia patients. We reviewed non-motor outcomes of DBS in dystonia, focusing on GPi-DBS.
Methods: A systematic literature search of Pubmed and Embase was performed according to the PRISMA guidelines.
Results: Fifty-two studies were included. GPi-DBS reduced pain related to dystonia. No major effects on anxiety, mood, and cognition were found. In contrast to motor outcome, non-motor outcome seems more independent of the etiology of dystonia. However, the impact of potential confounders (e.g. patient factors, changes in pharmacological treat-ment) is unclear.
Conclusion: Despite the growing interest in non-motor symptoms in dystonia, DBS studies still focus primarily on motor outcome. We recommend systematic evaluation of both non-motor and motor features before and after DBS interventions to improve quality of life and management of patients with dystonia.
INTRODUCTION
Over the past decades, deep brain stimulation of the globus pallidus internus (GPi-DBS) has emerged as an important treatment strategy in the management of medically intractable dystonias.[1] Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often patterned movements and/or postures and can be caused by a broad range of etiologies.[2] Motor outcome has been studied extensively, mainly in inherited and idiopathic isolated forms of dystonia.[3] In addition to motor symptoms, patients with dystonia frequently experience mood, behavioral, cognitive, sleep, and pain issues.[4,5] These non-motor symptoms (NMS) are most likely to be part of the dystonia phenotype as they can only partially be explained as secondary to motor impairment, or as medication side-effect. Irrespective of the precise pathogenesis, NMS might be at least as important as motor symptoms when it comes to the perceived disease burden.[6,7] GPi-DBS is targeted at the sensorimotor area, located in the postero-ventrolateral part of the GPi.[3] The possible (in)direct effects of GPi-DBS on the more antero-medial associa-tive and limbic regions are of interest, especially because of their integration in subcor-tical-cortical circuits presumed to be important for executive functioning and behaviour. [8,9] Reports on the influence of GPi-DBS on NMS in dystonia are contradictory, reporting improvements as well as deteriorations.[10-13] This review aims to systematically describe the impact of GPi-DBS on NMS in dystonia. A brief review on the NMS effect of other DBS targets is also provided.
METHODS
A systematic literature search was independently performed by two authors (HE and SS) according to the PRISMA guidelines.[14] First all published articles regarding the effects of GPi-DBS in dystonia patients were searched, and later the articles reporting on the effects of DBS on NMS as primary or secondary outcomes were identified. Articles were extracted from Pubmed and Embase, covering a period from September 1999 until December 2017, using the following combination of MeSH terms and free text words: ‘deep brain stimulation’, ‘pallidal stimulation’, globus pallidus internus stimulation’ AND ‘dystonia’ (for full search strategy see supplement 1). Only English articles describing non-motor outcomes in quantitative outcome measures (including pre- and postoperative values and/or a percentage of change) were included in the review. Articles concerning DBS of the thalamus or the subthalamic nucleus (STN) were set aside for a separate evaluation.
Due to the small numbers direct comparison of outcomes of thalamic and STN DBS with studies on GPi-DBS were not possible.
The most relevant non-motor outcomes were identified based on two previously published reviews concerning the NMS of dystonia, and subdivided into four categories: pain, psy-chiatry, cognition, and others.[4,15] The level of evidence was reported in the conclusions according to the levels evidence for therapeutic studies from the centre for Evidence-based medicine (see supplement 1).[16]
To deal with the heterogeneity of dystonia patients, results are presented for the different types of dystonia according to the etiology classification axis for dystonia.[2] Based on the available literature on DBS in dystonia, results from inherited and idiopathic dystonia (e.g. DYT1, DYT11, inborn errors of metabolism), and acquired dystonia (CP, tardive dystonia) are discussed separately.
RESULTS
The systematic literature search revealed a total of 107 articles addressing the effec-tiveness of DBS upon one or more NMS (flowchart in supplement 1). Of these 107, 55 were excluded because of only qualitative data or overlap in patient population with other articles, leaving 52 eligible articles. RCTs and case series including more than five patients are discussed.
Pain
The effect of GPi-DBS upon pain in dystonia has been reported in 23 articles, using the Toronto Western Spasmodic Torticollis Rating Scale Pain Subscale (TWSTRS-P), the visual analogue scale (VAS), the Pediatric Pain Profile (PPP) and the Faces Pain Scale (Table 1).
Inherited and idiopathic dystonia
Most studies report on cervical dystonia, where the effects of GPi-DBS on pain were eval-uated in a total of 154 patients. A RCT (n = 62) reported no significantly higher reduction in pain in the neuro-compared to the sham-stimulation group at 3-month follow-up.[17] After 6 months of non-blinded stimulation the mean pain reduction was 52% (p < 0.001), which was higher than the reduction in dystonia symptom severity (28%). In addition, nine case series (n = 6–14) showed a mean pain improvement from 48% to 73% which remained stable at follow-up ranging between 12 and 64 months.[12,18-22]. No correlations between motor
and pain outcome were reported, but six case series highlighted a dissociation between motor and pain response in timing and/or the extent.[11,12,19,21,23,24]
In a RCT (n = 40) involving inherited or idiopathic generalized segmental dystonia, pain scores showed a larger reduction for neuro-stimulation patients in comparison to sham-stimulation patients (63% vs 0%, p < 0.001) at 3 months, which was maintained at 6-month and 5-year follow-up.[25,26] A case series (n = 24) found a mean pain improve-ment of 53%, comparable to the relief in motor symptoms.[27] Six cranio-cervical dystonia patients had a mean improvement of 39%, a bit lower than motor improvement (45–90%). [28]
Acquired dystonia
Eleven patients (six children) with various forms of acquired dystonia reported a pain reduction varying from 48% to 100%, which was in contrast to a limited motor response (6–21%).[29-31]
Discussion
Pain is one of the most disabling and frequently present complaints in dystonia. Remarkably, the extent of pain is often not explained by the dystonia severity.[32] Current evidence suggests that pain may be due to changes in the thalamo-cortico-basal ganglia loops, integrating the multiple aspects of pain (e.g. motor, emotional and cognitive responses to pain).[33]
To this day, no studies have systematically looked into the correlation between motor and pain outcome of GPi-DBS for dystonia patients. Yet, there is a repeatedly reported difference in pain and motor response, supporting a possible role of pallidal stimulation in central pain processing.[11,12,19,23,29,30,33,34]. Irrespective of the underlying patho-physiological mechanisms, this dissociation between pain and dystonia relief is intriguing, especially when it comes to the discussion regarding the effectiveness in acquired forms of dystonia, such as CP, where the motor outcome is less robust.[35,36] With pain being one of the most frequent complaints, this underscores the importance of a systematic evaluation of the effect of GPi-DBS on pain.
Although all studies used a medically refractory form of dystonia as inclusion criteria, the majority did not report, or only vaguely, on the continuation of botulinum toxin injections
or oral medication after DBS. Therefore, it is impossible to conclude whether the pain response is influenced by changes in pharmacological treatment.
Conclusions
GPi-DBS in dystonia is likely to reduce pain both on the short- (6 months) and long-term follow-up (up to 6 year). The effect seems independent of dystonia etiology, with a higher level of evidence in isolated generalized and cervical dystonia (class II) compared to cra-nio-cervical and acquired dystonia (class IV). Pain response is repeatedly reported to be dissociated from motor response. However, blinded or correlational studies of pain and motor outcome are lacking as well the potential effect of confounding factors (e.g. change in pharmacological treatment or patient related factors).
Ta bl e 1 . Q ua nt ita tiv e s tu di es r ep or tin g o n t he i m pa ct o f G Pi -D BS o n p ai n i n d ys to ni a Au th or D esig n (n ) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs In cl us io n c ri te ri a P ai n me as ur e FU in mth % o f i m pr ov em en t; pa in s co re ± SD ( ra ng e) p er m ea su re m ent p oint M ot or se ve ri ty me as ur e % o f i m pr ov em en t; m ot or s co re ± SD ( ra ng e) p er m ea su re m ent p oint Re m ar ks Inh er ite d a nd id io pa th ic fo ca l ce rv ica l d ys ton ia Ku lis evs ky 2000 [2 3] C ase se ries (2 ) Id io pa th ic c er vic al ; Ag e 3 5-60 ; D D 7-20 Be nz odia ze pi ne s, tri he xy phe ni dyl , BT X a nd a na lg es ic s uns uc ce ss ful VA S 0 17 75 % 81 21 Tsui s co re 11 % 19 17 – BT X w as c on tin ue d i n on e pa tie nt – D iss oci at io n b et w ee n pa in a nd m ot or r es po ns e W öhlr e 20 03 [8 1] C as e r epo rt (1) Id io pa th ic c er vic al ; Ag e 6 0; D D 7 M in im al e ff ec t B TX an d t rih ex yp he ni dyl VA S 0 9 10 0% 4 0 BF MDR S-M 83% 49 8.5 – Ri sp er id on e w as l ow er ed (8 v s 2 m g) Bi tt ar 20 05 [11 ] C ase se ries (6 ) Id io pa th ic c er vic al ; Ag e 3 8. 5 (2 3-68 ); D D 8 ( 3-18 ) M ed ic al ly re fra ct or y TW ST RS -P 24 59 % TW ST RS -S 58% – Pa in i m pr ov ed a s fi rs t sy m pt om i n t he m aj or ity K is s 20 07 [18 ] C ase se ries (10 ) Id io pa th ic c er vic al ; Ag e 5 8 ( 47-64 ); D D 1 7 ( 5-28 ) In iti al r es po ns e a nd su bs eq ue nt f ai lu re to B TX TW ST RS -P 0 12 66% ** 26 .6 ± 3 .6 9. 1 ± 1 3. 1 TW ST RS -S 44% ** 14 .7 ± 4 .2 8. 4 ± 4 .4 – N o B TX a ft er D BS – 2/ 8 p at ie nt s s to pp ed th ei r m ed ic at io n po st ope ra tiv el y Lo he r 20 08 [8 2] C ase se ries (4 ) Id io pa th ic c er vic al ; Ag e 2 8-52 ; D D 4 -6 An tic ho lin er gi cs in su ffi ci en t o r n ot to le ra te d TW ST RS -P 0 12 36 45% 37% 6 (3 -8 ) 3. 3 ( 0-6) 3. 8 (0 -8) TW ST RS -S 55 % 28 % 20. 5 ( 19 -2 2) 9. 3 ( 6-14 ) 14 .8 (1 0-20 ) – 1/ 4 i m pr ov em en t i n se ve rit y, n ot p ai n. – 2/ 4 i m pr ov em en t o n se ve rit y a nd p ai n Sa kas 20 09 [8 3] C as e r epo rt (1) Id io pa th ic c er vic al , Ag e 4 9; D D 7 Ph ar mac ol og ic al an d B TX i ns uffi ci en t TW ST RS -P 0 3 6 9 70 % 70 % 70 % 10 3 3 3 TW ST RS -S 69 % 81% 88% 16 5 3 2 – N o s pe ci fic d at a o n m ed ic at io n u se a nd co nt in ua tio n Je on g 20 09 [8 4] C ase se ries (6 ) Id io pa th ic c er vic al ; Ag e 5 4 ± 1 0; D D 6 ± 3 In su ffi ci en t b en efi t of B TX a nd o th er m ed ic al tr ea tm ent s TW ST RS -P 0 3 6 12 65 % ** 61% 73% 6. 0 ± 7 .1 5. 8 ± 2 .1 6. 2 ± 1 .3 4. 4 ± 0 .7 TW ST RS -S 65 % * 69 % 77% 23 .8 ± 6 .4 8. 6 ± 6 .4 7. 4 ± 4 .2 5. 6 ± 3 .0 – N o s pe ci fic d at a o n m ed ic at io n u se – N o d is so ci at io n i n p ai n an d mo tor re sp on se
6
Au th or D esig n (n ) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs In cl us io n c ri te ri a P ai n me as ur e FU in mth % o f i m pr ov em en t; pa in s co re ± SD ( ra ng e) p er m ea su re m ent p oint M ot or se ve ri ty me as ur e % o f i m pr ov em en t; m ot or s co re ± SD ( ra ng e) p er m ea su re m ent p oint Re m ar ks To rr es 20 10 [8 5] C as e r epo rt (1) Id io pa th ic c er vic al ; Ag e 7 ; D D 9 Re si st an t to m ed ic al a nd B TX tr ea tm ent TW ST RS -P 0 3 79 % 14 3 TW ST RS -S 41% 22 13 – N o B TX po st ope ra tiv el y C ac ci ol a 20 10 [19 ] C ase se ries (10 ) Id io pa th ic c er vic al ; Ag e 3 7-63 ; D D 2 -2 6 Fa ilu re o r ex ha us tio n o f m ed ic al t re at m en t in clu di ng B TX TW ST RS -P 0 37 58% ** 13 .4 (6 -1 8) 5. 4 ( 0-14 ) TW ST RS -S 67 % ** 23 .8 (1 6-28 ) 8. 4 ( 0-19 ) – D iss oci at io n b et w ee n pa in a nd m ot or r es po ns e in 4 /1 0 ( 3; > 25 % s ev er ity th an p ai n r es po ns e, 1 ; >2 5% p ai n t ha n s ev er ity im pr ove m en t) Sko gs ei d 20 12 [3 8] C ase se ries (8 ) Id io pa th ic c er vi ca l ; Ag e 5 5 ( 47-72 ); D D 8 (5 -2 0) N on r es po nd er s to BT X, c lo naz epam (7 /8 ), p arac et am ol an d o pi oids (5 /8 ) TW ST RS -P 0 3 6 12 73 % 60% 73% 15 (11 -1 9) 4 ( 0-14 ) 6 ( 0-14 ) 4 ( 0-7 ) TW ST RS -S 46% 50% 64% 28 ( 23 -3 1) 15 (6 -1 9) 14 (5 -2 4) 10 (2 -1 9) – 2/8 u se d a na lg es ic s pos t-D BS , c lo naz epam re duct ion in 5 /7 – N o B TX a ft er D BS su rg er y K im 2012 [20 ] C ase se ries (14 ) Id io pa th ic c er vic al ; Ag e 4 8 (2 1-69 ); D D 5 (1-13) D es pi te B TX a nd ph ar ma co lo gic al tr ea tm ent TW ST RS -P 0 1 6 12 24 49 % ** 60% ** 60% ** 67 % ** 9. 3 ± 2 .8 5. 1 4. 1 4. 1 3.5 TW ST RS -S 59 % *** 66% *** 78 % *** 78 % *** 15 .6 ± 4 .4 6.8 6.1 3.9 3.7 – N ot c er ta in i f B TX an d p ha rma co lo gic al tr ea tm en t w as c on tin ue d af te r D BS Ya ma da 20 13 [2 4] C ase se ries (8 ) Id io pa th ic c er vic al ; Ag e 4 4 (2 7-74 ); D D 1 0 (1 -14 ) 7/ 8 r ec ei ve d B TX pr eope ra tiv el y TW ST RS -P 64 87 % * TW ST RS -S 70 % * – O ra l m ed ic at io n c ha ng ed in 3 /8 – Pa in r el ie f w as d is tin ct fr om mo tor re sp on se – N ot c er ta in i f B TX w as co nt in ue d a ft er D BS
Au th or D esig n (n ) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs In cl us io n c ri te ri a P ai n me as ur e FU in mth % o f i m pr ov em en t; pa in s co re ± SD ( ra ng e) p er m ea su re m ent p oint M ot or se ve ri ty me as ur e % o f i m pr ov em en t; m ot or s co re ± SD ( ra ng e) p er m ea su re m ent p oint Re m ar ks Sa dn ic ka 20 13 [2 1] C ase se ries (11 ) Id io pa th ic c er vic al ; Ag e 5 6 ± 1 1; D D 1 6 ± 7 Al l B TX w ith v ar io us ef fe ct TW ST RS -P 0 26 56% ns 7. 4 ± 4 .5 2. 9 ± 3 .0 TW ST RS -S 61% ** 23 .0 ± 4 .9 9. 1 ± 4 .4 – N ot c er ta in i f B TX w as co nt in ue d a ft er D BS – St ab le o r w or se ne d p ai n (n =4 ) w ith r ed uc tio n (> 33 % , n =3 ) o r s ta bl e se ve rit y s co re ( n= 1) W al sh 20 13 [12 ] C ase se ries (10 ) Id io pa th ic c er vic al ; Ag e 5 6 ± 1 3; D D 1 0 ± 1 2 In su ffi ci en t e ff ec t o f m ed ic al t re at m en t an d B TX TW ST RS -P 0 12 24 26 60 52 % ns 54% * 60% ** 48% ns 12 .6 ± 6 .5 6. 9 ± 6 .4 6. 7 ± 6 .4 5. 4 ± 6 .4 8. 5 ± 4 .6 TW ST RS -S 41% * 50% ** 49 % ** 53% ** 21 .5 ± 4 .6 12 .5 ± 3 .6 11 .0 ± 5 .6 10 .9 ± 4 .8 9. 9 ± 4 .8 – Pa in d iff er ed f ro m se ve rit y r es po ns e, in so m e pa tie nt s – La te d et er io ra tio n i n pa in m ay b e d ue t o pr ogr ess iv e sp in al di se ase o r G Pi fu nc tio na l an ato m y Vo lk ma nn 20 14 [17 ] RCT (62) Id io pa th ic o r i nh er ite d ce rv ic al; N eu ro -s tim ul at io n (n= 32 ) Ag e 5 7 ± 1 0 D D 1 5 ± 8 ; Sham -s tim ul at io n (n= 30 ) Ag e 5 7 ± 1 1; D D 1 5 ± 6 >6 m on th s a ft er BT X t re at m ent TW ST RS -P (R CT ) TW ST RS -P (ope n) 0 3 0 3 0 6 49 % 27 % ns 52 % *** N eu ro -s tim 10 .8 ± 5 .3 6. 5 ± 5 .6 Sham -s tim 13 .6 ± 4 .6 9. 9 ± 5 .6 12 .2 ± 4 .7 6. 1 ± 5 .8 TW ST RS -S TW ST RS -S 26% 6% ** 28 % *** N eu ro -s tim 19 .9 ± 3 .7 14 .7 ± 5 .0 Sham -s tim 20 .9 ± 3 .3 19 .6 ± 3 .9 20 .4 ± 3 .5 14 .6 ± 5 .2 – Pa in i m pr ov ed i n b ot h ne ur a nd sh am -st im ul at io n, b ut n ot to a si gn ifi ca nt ly e xt en t i n t he tw o t re at m ent g ro ups . – N o B TX a ft er s ur ge ry . – O ra l m ed ic at io n f ro m 3 6 re du ce d t o 1 1 d iff er en t dr ug s a ft er 6 m on th s, no d et ai ls o n h ow m an y pa tie nt s
6
Au th or D esig n (n ) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs In cl us io n c ri te ri a P ai n me as ur e FU in mth % o f i m pr ov em en t; pa in s co re ± SD ( ra ng e) p er m ea su re m ent p oint M ot or se ve ri ty me as ur e % o f i m pr ov em en t; m ot or s co re ± SD ( ra ng e) p er m ea su re m ent p oint Re m ar ks In he ri te d a nd i di op at hi c s eg m en ta l a nd g en er al iz ed d ys to ni a K ra uss 20 03 [2 9] C ase se ries (2 ) Id io pa th ic g en era liz ed , Ag e 5 1-58 ; D D 1 2-39 Tri he xy ph en id yl in su ffi ci en t o r n ot to le ra te d VA S 0 3 12 24 35 % 65 % 65 % 14 9 5 5 BF MDR S-M 74 % 74 % 73 % 81 21 21 22 – Bo th s to pp ed o ra l me di ca tion 3 mon th s af te r D BS – Pa in r ed uc tio n i n b ot h >3 3% Ku ps ch 20 06 [25 ] RCT (40) Id io pa th ic o r i nh er ite d ge ne ra liz ed a nd se gm en ta l c er vi ca l; N eu ro -s tim ul at io n (n= 20 ) Ag e 4 1 ± 1 4; D D 2 2 ± 8 ; Sham -s tim ul at io n (n= 20 ) Ag e 3 8 ± 1 4; D D 1 7 ± 8 D es pi te o pt im al ph ar ma co lo gic al tr ea tm ent 5 y ea r d is ea se dura tio n VA S (R CT ) VA S (ope n) 0 3 0 3 0 6 63% 0% *** 60% *** N eu ro -s tim 4. 6 ± 2 .9 1. 7 ± 1 .7 Sham -s tim 4. 8 ± 2 .4 8 ± 2 .5 ; 4. 7 ± 2 .6 1. 7 ± 1 .8 BF MDR S-M 44% 5% *** 5% *** N eu ro -s tim 40 .2 ± 2 4. 9 24 .5 ± 2 2. 8 Sham - s tim 32 .6 ± 2 4. 3 31 .1 ± 2 4. 0 36 .4 ± 2 4. 6 20 .2 ± 1 8. 0 – 20 p at ie nt s r ec ei ve d m ed ic al t re at m en t a t en ro llm en t, a ve ra ge do sa ge r ed uc tio n w as 32 .1 % a t 6 m on th s w ith ce ss at io n i n 5 p at ie nt s (2 5%) – BT X i n 1 3 a t b as el in e, no d et ai ls a bo ut co nt in ua tio n Va lld eo rio la 20 10 [2 7] C ase se ries (2 4) Id io pa th ic o r i nh er ite d ge ne ra liz ed a nd se gm en ta l c er vi ca l; Ag e 3 0 ± 1 4; D D 1 0 ± 7 Fu nc tio na l lim ita tio n d es pi te be st m ed ic al tr ea tm ent Fa ce s P ai n Sc al e 0 6 12 54% 53% * 3. 95 ± 2 .9 1. 83 ± 2 1. 87 ± 1 .1 BF MDR S-M 58% *** 59 % *** 42 .2 ± 2 2 17 .6 ± 1 2 17 .5 ± 1 2 – M ed ic at io n f or d ys to ni a w er e g lo ba lly r ed uc ed af te r s ur ge ry Id io pa th ic c ra ni oce rv ica l d ys ton ia C ap ell e 20 03 [8 6] C as e r epo rt (1) Id io pa thi c c ra ni al -ce rv ic al ; Ag e 6 0; D D 5 Lo ss o f e ffi ca cy of B TX , m ed ic al tr ea tm en t l im ite d b y si de e ff ec t VA S 0 3 12 24 38% 38% 38% 8 5 5 5 BF MDR S-M 58% 58% 67% 18 7.5 7.5 6 – Pr eope ra tiv e m ed ic at io n w as s lo w ly t ap er ed o ff (tri he xy ph en id yl , t ia pri de , tet ra ze pa m , z op ic lo n) . Os tr em 20 07 [28] C ase se ries (6 ) Id io pa thi c c ra ni al -ce rv ic al ; Ag e 6 6 ( 52 -7 0) ; D D 8 (2 -2 0) Se ve re f un ct io na l im pa irm en t d es pi te op tim al m ed ic al m an ag em ent TW ST RS -P 0 6 39% ns 8. 1 ± 3 .9 5. 0 ± 4 .6 TW ST RS -S BF MDR S-M 56% * 72 % * 19 ± 4 8.4 ± 5 .5 22 ± 8 .3 6. 1 ± 4 .2 – M os t pa tie nt s c on tinu ed to t ake th e s am e m ed ic at io n, b ut B TX w as st op pe d i n 3 /4 p at ie nt s
Au th or D esig n (n ) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs In cl us io n c ri te ri a P ai n me as ur e FU in mth % o f i m pr ov em en t; pa in s co re ± SD ( ra ng e) p er m ea su re m ent p oint M ot or se ve ri ty me as ur e % o f i m pr ov em en t; m ot or s co re ± SD ( ra ng e) p er m ea su re m ent p oint Re m ar ks A cqu ire d d ys to ni a K ra uss 20 03 [2 9] C ase se ries (4 ) G en er al iz ed d ue t o ce re br al p al sy ; Ag e 4 1 ( 36 -4 6) ; D D 3 9 (2 4-44 ) Tri he xy ph en id yl w as t rie d b ut in su ffi ci en t o r n ot to le ra te d VA S 0 3 12 24 52 % 66% 66% 5. 8 (4 -9 ) 2. 8 ( 0-6) 2 (0 -5 ) 2 (0 -5 ) BF MDR S-M 11 % 27 % 21% ns 70 .5 ( 39 -8 2) 62 .5 (3 7-80) 50 .8 (3 5-7 2) 55 .8 ( 37-74 ) – D ru g d os ag e r ed uc tio n i n 2/ 4 p os t-D BS – Al l p ai n i m pr ov em en t >3 3% , m ot or im pr ov em en t < 33 % Gi m en o 20 12 [3 0] C ase se ries (6 ) G en er al iz ed d ue t o ce re br al p al sy ( 5) a nd glu ta ric a cid ur ia ty pe 1 ( 1) ; Ag e 1 0 ( 5-14 ); D D 1 0 (5 -14 ) PP P VA S 6 12 6 12 48% 55% 69% 80% BF MDR S-M 6. 3% 5. 9% – N o i nf or m at io n o n ph ar ma co lo gic al tr ea tm en t o r B TX – Pa in i m pr ov em en t (> 30 % ) i n 3 /3 m ea su re d at 6 m on th s a nd 4 /4 a t 12 m on th f ol lo w -u p Kw on 20 16 [3 4] C as e r epo rt (1) Po st -tra uma tic h em i; Ag e 4 7, D D 4 4 M ed ic al t re at m en t fa ile d t o a lle vi at e sy m pto m s VA S 0 6 60 10 0% 10 0% 5 0 0 BF MDR S-M 20 % 20 % 26 21 21 – N o i nf or m at io n o n ph ar ma co lo gic al tr ea tm en t o r B TX TW ST RS -P , T or on to W es te rn S pa sm od ic T or tic ol lis R at in g S ca le p ai n s ub sc al e ( ra ng e 0 -2 0) ; V AS , v is ua l a na lo gu e s ca le ( ra ng e 0 -1 0) ; P PP , p ae di at ric p ai n p ro fil e ( ra ng e 0 -6 0) ; TW ST RS -S , T or on to W es te rn S pa sm od ic T or tic ol lis R at in g S ca le s ev er ity s ub sc al e ( 0-35 ); B FM D RS -M , B ur ke -F ah n-M ar sd en d ys to ni a r at in g s ca le m ot or s ub sc al e ( 0-12 0) ; B TX , bo tu lin um to xin in je ct io ns ; ns no n-si gn ifi ca nt ; * p ≤0 .0 5; * * p ≤0 .0 1; * ** p≤ 0. 00 1
6
Psychiatric issues
Twenty articles have quantitatively reported on the effects of GPi-DBS on mood and behavior (Table 2). The most used depression scales were the Beck Depression Inventory (BDI), Hamilton Depression Scale (HDS), and the Montgomery-Asberg Depression Rating Scale (MADRS). Anxiety was measured by the Beck Anxiety Inventory (BAI).
Inherited and idiopathic dystonia
A postoperative depression rating score (n = 85) or DSM axis diagnosis (n = 20) was available in 105 cervical dystonia patients. One RCT (n = 62) found a significant higher BDI reduction in the neuro-versus sham-stimulation group at 3-month follow-up (31% vs 4%, p < 0.05).[17] Three case series (n ranged from 5 to 10) that excluded moderately and severe depressed patients reported a trend to, or a significant decrease between 28 and 59% in depression scores.[18,37,38] One prospective study (n = 20) that did not exclude depression found overall stable depressive and anxiety disorders up to 5 years of follow-up.[39] Depression rating scales were assessed in 130 generalized and segmental dystonia patients. A RCT (n = 40) found no significant difference in the BDI score changes after 3 months of neuro-versus sham-stimulation (39% vs 9%). Six months of GPi stimulation led to a mean reduction of 30% on the BDI scores that remained stable at 5-year follow-up. [25,38] Other case series (n ranged from 14 to 26) reported stable scores to mild improve-ments (−3%–27%), irrespective from whether depression was excluded.[27,39-41] Anxiety was assessed in 81 patients, with overall stable outcomes up to 5 years postoperatively. [25,38,39,41,42] Since the last review on neuropsychiatric outcome of GPi-DBS highlight-ing the occurrence of suicide post-DBS, one other suicide has been reported in a DYT1 generalized dystonia patient with a bipolar affective disorder and a good motor outcome (68%) after more than 2 years after DBS.[13,39]
Acquired dystonia
Medication-induced dystonia or tardive dystonia (TD) is the largest acquired dystonia group. Since the majority of these patients develops dystonia after using neuroleptic medication, most of them have a positive psychiatric history. Two case series (n = 9 and n = 19) reported a trend or significant improvement of 48% and 59% respectively on the MADRS scores after 12–18 months, but four patients needed hospitalization for a possible DBS-related period of depression, agitation, anxiety or mania.[43,44]
For dystonic CP, two case series (n = 13 and n = 4) found a 100% decrease in the HDS and stable psychiatric symptoms, although after DBS implantation anti-depressants were started for anxiety in 5/13 patients.[29,45] One suicide was reported in a depressed patient with a good motor response more than two years after combined Vim-GPi stimulation.[39]
Discussion
Over the past decades, the psychiatric aspects of dystonia have gained more attention due to the relatively high prevalence of depression, anxiety and OCD in dystonia patients.[4] These symptoms are only partially explained by motor symptoms, and therefore likely to be part of the dystonia phenotype.[4,5] Also, they show to be important influencing factors of the quality of life.[46] Interestingly, from a psychiatric perspective there is also increasing evidence for the role of dysfunction of the cortical-limbic-striatal circuit in psychiatric disorders such as depression.[5,47]
In dystonia patients with preoperative stable psychiatric symptoms, GPi-DBS seems to be safe. Most data is gathered in non-blinded studies comprising isolated, idiopathic or inher-ited dystonia, where the vast majority of patients did not experience onset or worsening of depressive symptoms. Although most studies excluded patients with moderate to severe depression, stable to improved mood and stable anxiety status were found in the two studies including patients with moderate to severe depression.[27,39] Mood improvement has been attributed to symptom relief, medication discontinuation or social impact.[39] However, as correlation studies between motor and psychiatric outcome are lacking, an intrinsic action of stimulation on subcortical limbic loops implicated in depression cannot be excluded.
Interestingly, although the presence of psychiatric symptoms is frequently highlighted in DYT11 myoclonus dystonia, there is no controlled study in this patient group. Moreover, except from a report on worsening of psychiatric issues as well as one alleviation of panic attacks, no quantitative data is available for myoclonus dystonia.[48-50] Another distinct group is formed by Lesch-Nyhan patients, in which GPi-stimulation was repeatedly asso-ciated with decrease or disappearance of self-mutilating behavior, suggesting a central role for the GPi in behavioral networks.[51-54]
In acquired dystonias, case series report overall stable to mildly improved mood scores in patients with TD or dystonic CP.[44,45,55] Although based on case series, psychiatric disturbances or exacerbations were reported in 5/17 CP patients and 8/29 TD patients
during pallidal stimulation. However, patient samples were small and the associations between psychiatric disturbances and motor outcome are unclear. Nevertheless, these reports underscore the importance of careful psychiatric evaluation before and during DBS-treatment in this group of patients, and more thorough research on the possible pallidal stimulation effects on psychiatric symptoms.
Two suicides were reported in the past five years (one DYT1 and one CP patient), with no data to support a possible association between surgery and the suicide.[39] With an increasing number of DBS surgeries being performed in dystonia patients, the only small number of suicides might suggest that more attention has been paid to possibly vulnerable patients and consequently the prevention of suicide.
Conclusions
GPi-DBS appears a safe treatment option with regards to psychiatric outcomes in isolated, idiopathic or inherited dystonia patients with stable psychiatric symptoms (class II) as well as moderately to severe depressed patients (class IV). Despite only small reports (class IV), worsening of depression and anxiety during DBS treatment might occur more frequently in TD, DYT11 myoclonus dystonia and CP, highlighting the need for careful evaluation and follow-up of these patients.
Ta bl e 2 Q ua nt ita tiv e s tu di es r ep or tin g o n t he i m pa ct o f G Pi -D BS o n p sy ch ia tr ic s ym pt om s i n d ys to ni a Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks Inh er ite d a nd id io pa th ic fo ca l ce rv ica l d ys ton ia K ra uss 20 02 [3 7] C ase se ries (5 ) Id io pa th ic c er vic al ; Ag e 4 6 ( 36 -5 8) ; D D 1 2-44 D ep res si on (H D S) 0 3 6 12 20 50% 37% 37% 67% 9 4.5 ns 5.7 ns 5.7 ns 3 ns TW ST RS -S 38% 53% 55% 63% 20 .5 12 .7 ** 9.7 ** 9. 2 ** 7. 5 ** – H D S i m pr ov ed w ith m ot or s co re im pr ove m en t – N o a nt id ep re ss ant s K is s 20 07 [18 ] Pr os pe ct iv e ca se se ries (10 ) Id io pa th ic c er vic al ; Ag e 5 8 ( 47-64 ); D D 1 7 (5 -2 8) Pr es en ce o f ps yc hi at ric dis tu rb an ce s D ep res si on (B D I) 0 12 59 % *** 14 .2 ± 7 .2 6. 0 ± 3 .5 TW ST RS -S 44% ** 14 .7 ± 4 .2 8. 4 ± 4 .4 – N o a nt id ep re ss ant s Sko gs ei d 20 12 [3 8] C ase se ries (8 ) Id io pa th ic c er vic al ; Ag e 5 5 ( 47-72 ); D D 8 (5 -2 0) U ns ta bl e de pr es sio n D ep res si on (B D I) 0 18 28 % ns 9 ( 0-17 ) 6. 5 (0 -2 4) TW ST RS -S 73 % * 28 ( 23 -3 1) 7 ( 3-19 ) – At b as el in e 3 /8 m ild d ep re ss iv e, at f ol lo w u p, 2 /8 m od er at e Vo lk ma nn 20 14 [17 ] RC T (6 2) Id io pa th ic o r i nh er ite d ce rv ic al; N eu ro -s tim ul at io n (n= 32 ) Ag e 5 7 ± 1 0 D D 1 5 ± 8 ; Sham -s tim ul at io n (n= 30 ) Ag e 5 7 ± 1 1; D D 1 5 ± 6 M od er at e to s ev er e de pr es sio n (B D I>2 5) D ep res si on (B D I - R C T) Ps yc hi at ric sy m pto m s (B PR S-R C T) D ep res si on (B D I ope n) Ps yc hi at ric sy m pto m s 0 3 0 3 0 3 0 3 0 6 0 6 31% 4% * 7% 8% ns 21% ** 9% ** N eu ro -s tim 10 .8 ± 6 .2 7. 4 ± 6 .1 Sham -s tim 9. 8 ± 5 .8 9. 4 ± 6 .4 N eu ro -s tim 26 .5 ± 9 .4 24 .7 ± 5 .8 Sham -s tim 25 .6 ± 5 .8 23 .5 ± 5 .9 10 .3 ± 6 .0 8. 1 ± 6 .8 26 .0 ± 7 .8 23 .6 ± 5 .1 TW ST RS -S TW ST RS -S 26% 6% ** 28 % *** N eu ro -s tim 19 .9 ± 3 .7 14 .7 ± 5 .0 Sham -s tim 20 .9 ± 3 .3 19 .6 ± 3 .9 20 .4 ± 3 .5 14 .6 ± 5 .2 – Th re e p os sib le s tim ul at io n re la te d d ep re ss io ns o f w hi ch tw o r es ol ve d a nd o ne n ee de d pa tie nt c ou nse llin g
6
Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks M eo ni 20 15 [3 9] C ase se ries (2 0) Id io pa th ic c er vic al ; Ag e 5 4 ± 1 0; D D 1 5 ± 1 4 Ps yc ho sis or s ui ci da l id eat io n D SM I V – a xi s I dia gn os is 0 28 14 d ia gn os es 13 d ia gn os es TW ST RS -S 51% *** 23 .1 ± 3 .2 11 .6 ± 4 .9 – 11 u nc ha ng ed , 3 r em is si on , 2 new -o ns et – M oo d a nd a nx ie ty d is or de rs st ab le , o ne a nx ie ty a fte r ces sa tio no f b en zo di az ep in es . In he ri te d a nd i di op at hi c s eg m en ta l a nd g en er al iz ed d ys to ni a C ap ell e 20 03 [8 6] C as e r epo rt (1) Id io pa thi c c ra ni al -ce rv ic al ; A ge 6 0; D D 5 D ep res si on (H D S) 0 3 12 24 -2 9% 18 % 24% 17 22 14 13 BF MDR S-M 58% 58% 67% 18 7.5 7.5 6 K ra uss 20 03 [2 9] C ase se ries (2 ) Id io pa th ic g en era liz ed , Ag e 5 1-58 ; D D 1 2-39 Ma jor ps yc hi at ric dis or de rs D ep res si on (H D S) 0 3 12 24 57% 64% 79% 14 6 5 3 BF MDR S-M 74 % 74 % 73 % 81 21 21 22 – Pr eope ra tiv el y o ne m od er at e an d o ne m ild d ep re ss iv e s co re t o no rm al a t 2 -y ea r f ol lo w -u p w ith go od mo tor re sp on se Vid ai lh et 20 05 [4 0] C ase se ries (2 2) Id io pa th ic a nd i nh er ite d ge ne ra liz ed dy st on ia ; Ag e 3 0 ( 14 -5 4) ; D D 1 8 (4 -3 7) Ps yc hi at ric dis tu rb an ce s D ep res si on (B D I) 0 12 27 % ns 11 ± 7 8 ± 8 BF MDR S-M 55 % *** 46 .3 ± 2 1. 3 21 .0 ± 1 4. 1 – 3/ 5 p at ie nt s s top pe d ant id ep re ss ant s – Sc or es s ta bl e a t 3 -y ea r F U [ 87 ]
Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks Ku ps ch 20 06 [25 ] RC T (4 0) Id io pa th ic o r i nh er ite d ge ne ra liz ed a nd se gm en ta l c er vi ca l; N eu ro -s tim ul at io n (n= 20 ) Ag e 4 1 ± 1 4; D D 2 2 ± 8 ; Sham -s tim ul at io n (n= 20 ) Ag e 3 8 ± 1 4; D D 1 7 ± 8 M od er at e to s ev er e de pr es sio n (B D I> 25 ) a nd no ps yc hi at ric co -e xi ste nt dis or de rs D ep res si on (B D I-R C T) An xi et y (B AI -R C T) Ps yc hi at ric sy m pto m s (B PR S-R C T) D ep res si on (B D I-ope n) An xi et y (B AI -ope n) Ps yc hi at ric sy m pto m s (B PR S-ope n) 0 3 0 3 0 3 0 3 0 3 0 3 0 6 0 6 0 6 39 -9% ns 42 % 13 % ns 21% 11% 30% ** 27 % ns 8% ns N eu ro -s tim 10 .5 ± 7 .3 6. 4 ± 8 .9 Sham -s tim 9. 7 ± 5 .8 10 .6 ± 1 0. 1 N eu ro -s tim 13 .7 ± 1 1. 0 8. 0 ± 6 .5 Sham -s tim 12 .1 ± 1 0. 5 10 .5 ± 7 .4 N eu ro -s tim 27 .0 ± 7 .3 21 .4 ± 4 .6 Sham -s tim 27 .8 ± 8 .0 24 .8 ± 5 .5 10 .1 ± 6 .5 7.1 ± 6 .7 12 .9 ± 1 0. 7 9. 4 ± 7 .6 27 .4 ± 7 .6 25 .3 ± 7 .1 BF MDR S-M 44% 5% *** 45% *** N eu ro -s tim 40 .2 ± 2 4. 9 24 .5 ± 2 2. 8 Sham - s tim 32 .6 ± 2 4. 3 31 .1 ± 2 4. 0 36 .4 ± 2 4. 6 20 .2 ± 1 8. 0 – Im pr ov em en ts i n m oo d re m ai ne d s ta bl e a t 5 -y ea r F U [ 26 ]
6
Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks Va llde ori ol a 20 10 [2 7] C ase se ries (2 4) Id io pa th ic o r i nh er ite d ge ne ra liz ed a nd se gm en ta l; Ag e 3 0 ± 1 4; D D 1 0 ± 7 Ac tiv e ps yc hi at ric sy m pto m s D ep res si on (B D I) 0 6 12 18 % 22 % * 34 .9 ± 1 2. 3 28 .7 ± 9 .6 27 .1 ± 1 1. 0 BF MDR S-M 58% *** 59 % *** 42 .2 ± 2 2 17 .6 ± 1 2 17 .5 ± 1 2 – M oo d m ild ly im pr ov ed , p os sib ly se con da ry to mo tor re sp on se, bu t n o r ep or t o n a ss oc ia tio ns mo tor a nd mo od re sp on se Jah an sh ah i 20 14 [4 1] (14 ) Id io pa th ic o r i nh er ite d ge ne ra liz ed ; Ag e 4 2 ± 1 9; D D 2 4 ± 1 7 D ep res si on (B D I) An xi et y (B AI) 0 14 0 14 -3% ns -4% ns 7. 2 ± 4 .3 7. 4 ± 6 .4 11 .9 ± 5 .9 12 .4 ± 1 0. 3 BF MDR S-M 69 % *** 39 .9 ± 1 7. 4 13 .3 ± 1 1. 6 – N or m al B DI a nd o nl y m ild an xi et y o n B AI a t b as el in e M eo ni 20 15 [3 9] C ase se ries (2 6) Id io pa th ic o r i nh er ite d ge ne ra liz ed a nd se gm en ta l c er vi ca l; Ag e5 4 ± 1 9; D D 2 4 ± 1 5 Ps yc ho sis or s ui ci da l id eat io n D SM I V – a xi s I dia gn os is 0 22 13 d ia gn os es 9 d ia gn os es BF MDR S-M 67 % *** 31 .9 ± 1 7. 4 20 .4 ± 2 2. 4 – 8 u nc ha ng ed , 5 i n r em is si on 1 new -o ns et – M oo d t re nd t o i m pr ov em en t, pos sib ly se co nd ar y t o m ot or be ne fit , p ai n r ed uc tio n a nd /o r m ed ic at io n d is co nt in ua tio n – Stab le an xi et y, 1 sui ci de A cqu ire d d ys to ni a ( Var iou s) M eo ni 20 15 [3 9] C ase se ries (11 ) Var io us a cquir ed di so rd er s; A ge 3 7 ± 4 ; D D 1 9 ± 5 Ps yc ho sis or s ui ci da l id eat io n D SM I V – a xi s I dia gn os is 0 10 10 d ia gn os es 9 d ia gn os es BF MDR S-M 32 % ** 34 .9 ± 2 2. 1 23 .8 ± 2 0. 7 – 8 u nc ha ng ed , 2 r em is si on , 1 new -o ns et – M oo d a nd a nx ie ty d is or de rs st ab le , o ne a nx ie ty e pi so de a fte r to b en zo di az ep in es c es sa tio n. – 1 sui ci de A cq ui re d d ys to ni a ( C er eb ra l p al sy) K ra uss 20 03 [2 9] C ase se ries (4 ) G en er al iz ed ; Ag e 4 1 ( 36 -4 6) ; D D 3 9 (2 4-44 ) D ep res si on (H D S) 0 3 12 24 25 % 89% 100% 7. 5 ( 0-12 ) 5. 6 ( 1-15 ) 0. 8 ( 0-2 ) 0 BF MDR S-M 11 % 27 % 21% ns 71 ( 39 -8 2) 63 (3 7-80) 51 (3 5-7 2) 56 ( 37-74 ) – O ne m ild d ep re ss iv e sc or e pr eope ra tiv el y t o n or m al w ith sm al l m ot or b en efi t.
Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks Vid ai lh et 20 09 [4 5] C ase se ries (1 3) G en er al iz ed ; Ag e 3 3 (2 0-44 ) Ps yc hi at ric dis or de rs Ps yc hi at ric sy m pto m s (H op ki ns ch eck lis t) 12 28 % ns 34 .0 ± 9 .3 24 .6 ± 1 5. 5 BF MDR S-M 21% ** 44 .2 ± 2 1. 1 34 .7 ± 2 1. 9 – Tr en d t o i m pr ov em en t O CD , de pr ess iv e, p ara no id , p sy ch ot ic sy m pt oms an d s tab le an xi et y, an ge r, s le ep . – 5/1 3 a nt i-d ep re ss an ts A cqu ire d d ys to ni a ( Tar di ve d ys to ni a) Kose l 20 06 [8 8] C as e r ep or t (1) Ta rd iv e d ys to ni a; Ag e 6 2; D D 1 0 D ep res si on (B D I) D ep res si on (MA D RS ) 0 18 0 18 22 17 26 13 BF MDR S-M 35 % 27 17.5 – D ep re ss iv e s ym pt om s si gn ifi ca nt ly i m pr ov ed i n se ve re ly d ep res se d pa tie nt G rub er 20 09 [4 3] C ase se ries (9) Ta rd iv e d ys to ni a; Ag e 6 3 ± 1 3; D D 5 ± 3 Ac ute ps yc hi at ry , MA D RS > 29 D ep res si on (MA D RS ) 0 18 59 % ** 14 .2 ± 7 .0 6. 5 ± 5 .3 BF MDR S-M 82 % *** 30 .9 ± 1 2. 1 5. 5 ± 4 .8 Po uc let -C ou tr em anc he 20 16 [4 4] C ase se ries (19 ) Ta rd iv e d ys to ni a; Ag e 5 2 (2 5-69 ); D D 6 ( 1-38 ) PA N N S < 50 D ep res si on (MA D RS ) Sch iz op hr en ia (P A N SS ) 12 48% ns 10 % ns 14 .5 ± 1 0. 9 7. 6 ± 4 .8 50 .1 ± 1 5. 5 45 .4 ± 1 6. 9 ES RS 58% – Ei gh t p os sib le D BS -re la te d ps yc hi at ric s id e e ff ec ts : de pr ess io n ( 4), a nx iet y ( 1), ma ni a (1 ), d el iri um ( 1) a nd a gi ta tio n ( 1) 4 ne ede d h os pi ta liz at io n
6
Au th or D es ig n ( n) D ia gn os is ; a ge a nd ; di se as e d ur at io n ( D D) in y ea rs Ex cl us io n cr ite ri a Sy m pt om (o ut com e me as ur e) Fo llo w up i n mo nt hs % o f i m pr ov em en t; sc or e ± S D ( ra ng e) p er me as ur eme nt M ot or se ve ri ty me as ur e % o f i m pr ov em en t; sc or e ± S D ( ra ng e) pe r me as ur eme nt Re m ar ks Va rio us e tio lo gi es H albi g 20 05 [42 ] C ase se ries (1 5) Id io pa th ic , i nh er ite d a nd ta rd iv e d ys to nia ; Ag e 4 6 ( 13 -3 8) ; D D 1 3 ( 6-62 ) La ck o f co ope ra tio n D ep res si on (B D I) D ep res si on (MA D RS ) An xi et y (B AI) An he do ni a (SH PS ) M ani a (B R M RS) Ps yc hi at ric sy m pto m s (B PR S) 0 7 0 7 0 7 0 7 0 7 0 7 24% ns 48% ** 27 % ns 69 % * 67 % * 30% ns 13 .6 ± 9 .5 9. 4 ± 1 1. 3 13 .3 ± 7 .7 7. 7 ± 7 .7 15 .0 ± 1 2. 8 10 .9 ± 1 2. 3 1. 6 ± 1 .1 0. 5 ± 0 .7 1. 2 ± 1 .6 0. 4 ± 1 .3 27 .7 ± 1 1. 4 19 .4 ± 8 .5 BF MDR S-M 71% *** 33 .8 ± 1 3. 7 13 .7 ± 1 0. 7 – SH PS a nd B PR S n or m al pr eope ra tiv el y – Al l ha d im pr ov ed d ep res sio n sc or es ( 3/ 15 o n B DI a nd 2 /1 5 on M AD RS ) a ls o s ho w ed a si gn ifi ca nt m ot or r es po ns e – O ne d et er io ra tio n o n B DI w ith go od m ot or r es po ns e, b ut n o ex ac t s co re s w er e g iv en . D e G us m ao 20 17 [8 9] C ase se ries (12 ) Fo ca l, s eg m en ta l a nd ge ne ra liz ed d ys to ni a o f in he rit ed , i di op at hi c a nd ta rd iv e; A ge 4 2. 3; D D 1 0. 1 N ot a n i nt ac t cog nit io n D ep res si on (B D I) An xi et y (B AI) H op el essn ess (BH S) 0 13 0 13 0 13 -3 6% * 6% * 5% ns 10 .5 ± 8 .3 6. 6 ± 5 .7 10 .2 ± 1 3. 6 9. 6 ± 1 3. 6 2. 8 ± 2 .1 2. 6 ± 3 .3 BF MDR S-M 61% 21 .6 ± 1 1. 5 8. 4 ± 4 .6 – To ta l m ed ic at io n i nc re as e (1 ), s ta bl e ( 3) , r ed uc tio n ( 6) o r st op pe d ( 2) – N o i nf or m at io n o n t he cor re la tion b et w een mo tor /n on -m ot or o ut co m e a nd i nfl ue nc e o f me di ca tion A ES : A pa th y E va lu at io n S ca le ( 0-54 ); B AI , B ec k A nx ie ty I nv en to ry ( ra ng e 0 -6 3; 0 -7 m in im al , 8 -1 5 m ild , 1 6-25 m od er at e, 2 6-63 s ev er e a nx ie ty) ; B D I, B ec k D ep re ss io n I nv en to ry ( ra ng e 0 -6 3; 0 -9 m ild , 1 0-18 m in im al , 1 9-29 m od er at e, 3 0-63 s ev er e d ep re ss io n) ; B R M RS , B ec h– Ra fa el se n M an ia R at in g S ca le ( ra ng e 0 -4 4) ; B PR S, B rie f p sy ch ia tr ic r at in g s ca le ( ra ng e 1 8-12 6) ; H D S: H am ilt on D ep re ss io n S ca le ( ra ng e 0-56 , 0 -7 n or m al , 8 -1 3 m ild , 1 4-18 m od er at e, 1 9-22 s ev er e, > 23 v er y s ev er e) ; M A D RS , M on tg om er y– Ås be rg D ep re ss io n R at in g S ca le ( ra ng e 0 -6 0, 0 -6 n or m al , 7-19 m ild , 2 0-34 m od er at e, 3 5-60 s ev er e) ; PA N N S: P os iti ve a nd n eg at iv e S yn dr om e S ca le f or S ch iz op hr en ia ( ra ng e 3 0-21 0) ; S H PS : S na ith –H am ilt on P le as ur e S ca le ; S R PS S: S el f-ra te d p sy ch ia tr ic s ym pt om s ca le ; B FM D RS -M , B ur ke -F ah n-M ar sd en dy st on ia r at in g s ca le m ot or s ub sc al e ( 0-12 0) ; E SR S, E xt ra py ra m id al S ym pt om R at in g S ca le ; T W ST RS -S , T or on to W es te rn S pa sm od ic T or tic ol lis R at in g S ca le s ev er ity s ub sc al e ( 0-35 ); ns no n-si gn ifi ca nt ; * p≤ 0. 05 ; * * p ≤0 .0 1; * ** p≤ 0. 00 1
Cognitive issues
Twenty-two studies reported on examination of cognition before and after GPi-DBS in dystonia, using a large variety of cognitive tests including the Mini Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS). Studies of five or more patients are showed in Table 3.
Inherited or idiopathic isolated dystonia
In a total of 93 patients with cervical dystonia, no difference in global cognition scores were found between baseline and post-operative condition, and more extensive test batteries only reported a small decline in verbal memory and fluency of uncertain clinical relevance. [17,18,22,37]
Global cognition screening in 88 generalized and segmental dystonia patient remained stable during DBS treatment.[25,27,29,40] Three case studies (n = 14, 22 and 24), including one pediatric cohort, in which cognition was extensively tested, reported improvement in attention, memory, and executive functioning,[56,57] as well as slight worsening of verbal reasoning and memory.[41,57] Improvements were partially related to the decrease in anticholinergic medication and improved motor function.
Nine children with dystonia due to pantothenate-kinase-associated neurodegeneration (PKAN) were assessed at baseline and post-operatively at 24–36 months follow-up, showing overall stable to improved cognitive scores, presumably due to better concen-tration and the ability to finish more tests.[58,59] One patient deteriorated on almost all cognitive tests, which was attributed to disease progression.
Acquired dystonia
Global cognition, including MMSE and MDRS, was reported to remain stable during DBS treatment at 6–12 months follow-up in 19 TD patients.[44,60] One more extensive report in 9 TD patients found stable scores with a trend to improvement in verbal fluency.[43] For CP patients, one report in 40 pediatric DBS patients found no significant decline in scores postoperatively.[61]
Discussion
The antero-medial GPi is integrated in the dorsolateral prefrontal and lateral orbitofrontal circuit, connecting the basal ganglia with the prefrontal cortex.[8,9] The dorsolateral prefrontal circuit is important for executive functioning and motor planning, whereas
disruptions of the lateral orbitofrontal circuit can cause loss of interest and initiative. This probably explains why impairments in executive function, attention, verbal memory, and sequence learning have been frequently reported in dystonia patients, especially in DYT1, idiopathic cervical dystonia and DYT11 patients.[62-65] However, these findings have not always been consistent, and might be partially attributed to medication, discomfort, and depressive symptoms.
Based on the existing studies, GPi-DBS appears to have no major impact on the cognition of dystonia patients. These conclusions should be taken with caution in absence of blinded case-controlled studies and the heterogeneity of the neuropsychological assessments across studies. Although more thoroughly investigated in isolated generalized dystonia compared to acquired dystonia, the reported stability of cognitive functioning seems to be irrespective of the underlying dystonia etiology. Slight improvement in executive functioning and memory was reported in various dystonias.[42,56-58,66]. However, the (additional) influence of learning effects on the tasks, decrease in medication (anticholinergics) and/ or improved motor status upon reported improvements cannot be distinguished from the effects of GPi-DBS. Only one case series controlled for the use of medication by unchanged drug intake between baseline and follow-up.[41] These authors found no changes across multiple domains of cognitive function, except for worsening in sustained attention. This might be explained by a disturbance in the dorsolateral prefrontal circuit, but more studies are required to study this aspect and the consequences for daily functioning.[67]
Conclusions
Based on current evidence, despite the unknown influence of changes in medication and the heterogeneity in cognitive assessments across the studies, GPi-DBS does not have major impact on the cognition of dystonia patients (class IV). This stability seems to be irrespective of the underlying dystonia etiology.
Ta bl e 3 St ud ie s r ep or tin g o n t he i m pa ct o f G Pi -D BS o n c og ni tio n i n d ys to ni a Au th or D es ig n ( n) D ia gn os is ; a ge an d; di se as e dura tio n (D D) i n y ea rs Fo llo w -up i n mo nt h Ex cl us io n cr ite ri a C og ni tiv e f un ct io n (me as ur e) C og ni tiv e o ut co m e M ea n % of m ot or imp ro ve m ent C ha ng e i n m ed ic at io n Re m ar ks Inh er ite d a nd id io pa th ic fo ca l ce rv ica l d ys ton ia K ra uss 20 02 [3 7] C ase se ries (8 ) Id io pa th ic c er vic al ; Ag e 4 6 ( 36 -5 8) ; D D 12 -4 4 20 G lob al c og nit io n (M M SE ) N on si gn ifi ca nt i nc re as e o f M M SE f ro m 2 7 to 3 0 63% (BFMDR S) N o d et ai ls o n co nt in ua tio n o f or al me di ca tion – Lo w er M M SE p re -op er at iv el y p ar tly d ue to in te rf er in g m oto r sy m pto m s K is s 20 07 [18 ] C ase se ries (10 ) Id io pa th ic c er vic al ; Ag e 5 8 ( 47-64 ); D D 17 (5 -2 8) 12 Ab no rm al cog nit io n Tes t ba tt er y O ve ra ll n o s ig ni fic an t ch an ge s e xc ep t f ro m sm al l d ec lin e i n v er ba l m em or y a nd le ar ni ng (n =3 ) 44% ** (T W ST RS -S) N o B TX a nd 2 /8 st op pe d t he ir me di ca tion – U nc er ta in c lin ic al re le va nc e o f c ha nge s – O ne p at ie nt h ad w or se ni ng o f d ys to ni a an d d ep res sio n Vo lk ma nn 20 14 [17 ] RC T, ope n la be l (6 2) Id io pa th ic o r in he rit ed c er vi ca l; Ag e 5 7 ± 1 0; D D 15 ± 7 6 M D RS <1 20 G lob al c og nit io n (MDR S) St ab le s co res 28 % *** (T W ST RS -S) O ra l m ed ic at io n re du ce d f ro m 36 t o 1 1 – O bs er ve d n o c ha ng es in c og ni tiv e s ta tu s, n o de -n ov o b eh av io ra l ab no rm al ities D in ke lb ac h 20 15 [2 2] C ase se ries (1 3) Id io pa th ic c er vic al , Ag e 5 4 ± 1 2; D D 15 ± 9 12 M D RS <1 20 M em or y, e xe cu tiv e fu nct ion , a tt en tion , vi su al pe rc ep tio n, m en ta l a rit hm et ic , ve rb al in te lli ge nc e (te st b at te ry ) N o c ha ng es , e xc ep t f ro m a d et er io ra tio n o f v er ba l flu en cy t as k ( co gn iti ve flex ib ili ty ) O ra l m ed ic at io n st ab le (2 ), re du ce d ( 1) o r st opp ed (6 ) – D et er io ra tio n n ot co rr el at ed w ith c ha ng e in d ys to ni a s ev er ity o f qu al ity o f l ife In he ri te d a nd i di op at hi c s eg m en ta l a nd g en er al iz ed d ys to ni a M or ris on 2000 [9 0] C ase se ries (2 ) U nk no w n, A ge 31 -3 2; D D 5 -2 1 1 Ab no rm al IQ At te nt io n, L an gu ag e, vis uo -s pa tia l, e xe cu tiv e, ve rb al l ea rn in g, r ec al l, me mor y O ne p at ie nt s ho w ed im pr ov em en t o n a tt en tio n an d v er ba l r ec al l. U nk now n (B FMDR S) U nk now n C ap ell e 20 03 [8 6] C as e r epo rt (1) Id io pa thi c c ra ni al -ce rv ic al ; A ge 6 0; D D 5 24 G lob al c og nit io n (M M SE ) M M SE i m pr ov ed f ro m 24 t o 2 8 67 % (B FMDR S) Me di ca tio n w as t ap er ed o f sl ow ly
6
Au th or D es ig n ( n) D ia gn os is ; a ge an d; di se as e dura tio n (D D) i n y ea rs Fo llo w -up i n mo nt h Ex cl us io n cr ite ri a C og ni tiv e f un ct io n (me as ur e) C og ni tiv e o ut co m e M ea n % of m ot or imp ro ve m ent C ha ng e i n m ed ic at io n Re m ar ks K ra uss 20 03 [2 9] C ase se ries (2 ) Id io pa thi c ge ne ra liz ed , A ge 51 -5 8; D D 1 2-39 24 G lob al c og nit io n (M M SE ) St ab le s co res 79 % (B FMDR S) 2/ 2 a bl e t o s to p ant id ys to ni c dr ug s Vid ai lh et 20 05 [4 0] C ase se ries (2 2) Id io pa thi c an d i nh er ite d ge ne ra liz ed ; A ge 30 ( 14 -5 4) ; D D 1 8 (4 -3 7) 12 M M SE < 24 G lob al c og nit io n (M M SE ) St ab le s co res 55 % *** (B FMDR S) O ra l m ed ic at io n in cr ea se d (3 ), s ta bl e ( 4) , re du ce d ( 11 ) o r st op pe d ( 2) – N o d et ai ls o n ass oci at io n b et w ee n ce ss at ion or re duct ion in m ed ic at io n a nd co gn iti ve o ut com e Ku ps ch 20 06 [25 ] RC T, ope n la be l (4 0) Id io pa thi c or i nh er ite d ge ne ra liz ed a nd se gm en ta l c er vi ca l; Ag e 3 9 ± 1 4; D D 20 ± 8 6 M D RS <1 20 G lob al c og nit io n (MDR S) St ab le s co res 45% *** (B FMDR S) D os ag e re duct ion 3 2% Pill on 20 06 [5 6] C ase se ries (2 2) Id io pa thi c or i nh er ite d ge ne ra liz ed ; A ge 30 ( 14 -5 4) ; D D 1 8 (4 -3 7) 12 M M SE < 2 4 G lob al c og nit io n, abs tr ac t r ea so ni ng , ve rb al l ea rn in g, fl ue nc y, ex ec ut iv e fu nc tio ni ng (te st b at te ry ) M ild b ut s ig ni fic an t im pr ov em en t o n re as on in g, e xe cu tiv e fu nct ion in g a nd me mor y. 55 % *** Si gni fic ant re duct ion in m ed ic al tr ea tm ent – Po ss ib ly p ar tly d ue t o be tt er mo tor fu nct ion an d d ec re as e i n d ru gs an d le ar ni ng e ff ec t. – St ab le r es ul ts a t 3 -y ea r fo llo w u p ( Vi da ilh et , 20 07 ) Va llde ori ol a 20 10 [2 7] C ase se ries (2 4) Id io pa thi c or i nh er ite d ge ne ra liz ed a nd se gm en ta l; Ag e 3 0 ± 1 4; D D 10 ± 7 12 M M SE < 24 G lob al c og nit io n (M M SE ) St ab le s co res 59 % *** (B FMDR S) Me di ca tio n w as g lo ba lly re du ce d a ft er su rg er y
Au th or D es ig n ( n) D ia gn os is ; a ge an d; di se as e dura tio n (D D) i n y ea rs Fo llo w -up i n mo nt h Ex cl us io n cr ite ri a C og ni tiv e f un ct io n (me as ur e) C og ni tiv e o ut co m e M ea n % of m ot or imp ro ve m ent C ha ng e i n m ed ic at io n Re m ar ks Jah an sh ah i 20 14 [4 1] C ase se ries (14 ) Id io pa thi c or i nh er ite d ge ne ra liz ed ; Ag e 4 2 ± 1 9; D D 24 ± 1 7 14 G lo ba l c og ni tio n, I Q , me mor y, l an gu ag e, ex ec ut iv e f un ct io n, t as k sw itc hi ng a nd a tt en tio n (te st b at te ry ) N o c ha ng es i n I Q , m em or y, l an gu ag e a nd ex ec ut iv e f un ct io n. O nl y si gn ifi ca nt w or se ni ng o f sus ta in ed a tt en tio n. 69 % *** (B FMDR S) N o c ha ng es i n m ed ic at io n a t ba se lin e a nd fo llo w -up – N o e ff ec t o f DY T1 u po n co gn iti ve o ut com e. O w en 20 15 [5 7] C ase se ries (1 3) Id io pa thi c or i nh er ite d ge ne ra liz ed , 1 2 ± 4 12 N on -v er ba l a nd v er ba l in te lle ct ual a bili tie s, m em or y a nd p ro ce ss in g sp ee d ( te st b at te ry) O ve ra ll s ta bl e a nd im pr ov ed s co re s, e xc ep t fr om d et er io ra tio n i n ve rb al c om pr eh en si on ( 1) , re as on in g ( 1) a nd v er ba l o r vi su al m em or y (2 ) O ra l m ed ic at io n re du ce d ( 5) o r st op pe d ( 2) – 4/ 5 w ith r ed uc ed an tic ho lin er gi cs im pr ov ed o n c er ta in do m ai ns – Im pr ov ed m ot or fu nc tio n l ike ly t o h av e co nt rib ut ed P an to the nat e-ki na se -a ss oc iat ed n eu ro de ge ne rat io n M ah on ey 20 07 [5 8] C ase se ries (7) G en er al iz ed , PA N K 2; Ag e 1 2 ( 8-17 ); D D 7 ± 3 24 N on -v er ba l a nd in te lle ct ual a bili tie s, m em or y ( te st b at te ry) St ab le s co re s a nd im pr ov em en t i n a ll b ut o ne N o d et ai ls ab ou t o ra l me di ca tion – Be tt er s co re s d ue t o be tt er co nce nt ra tio n an d a cc es s to t es t m ate ria ls . – W or se ( 1) d ue t o de te rio ra tio n i n dys to ni a Ad am ov ic ov á 20 11 [5 9] C ase se ries (2 ) G en er al iz ed , PA N K 2; Ag e 1 7-18 ; D D 9 36 IQ , v er ba l l ea rn in g, ex ec ut iv e f un ct io n, ve rb al fl ue nc y ( te st ba tte ry ) IQ s ta bl e, v er ba l l ea rn in g, ex ec ut iv e fu nc tio ni ng a nd ve rb al fl ue nc y b et te r ( 1) o r w or se ne d ( 1) 40% (BFMDR S) M ed ic at io n w as re du ce d i n b ot h A cq ui re d d ys to ni as ( C er eb ra l p al sy ) K ra uss 20 03 [2 9] C ase se ries (4 ) G en er al iz ed d ue t o ce re br al p al sy ; A ge 41 ( 36 -4 6) ; D D 3 9 (2 4-44 ) 24 C ogn iti on (M M SE ) St ab le M M SE s co res Be nz odia ze pi ne re du ct io n i n 2 /4 po st -D BS
6
Au th or D es ig n ( n) D ia gn os is ; a ge an d; di se as e dura tio n (D D) i n y ea rs Fo llo w -up i n mo nt h Ex cl us io n cr ite ri a C og ni tiv e f un ct io n (me as ur e) C og ni tiv e o ut co m e M ea n % of m ot or imp ro ve m ent C ha ng e i n m ed ic at io n Re m ar ks O w en 20 17 [6 1] C ase se ries (4 0) D ysk in et ic C P, dy st on ia c au se d by I EM ; Ag e 1 2. 5 ± 3 .5 12 N on -v er ba l a nd v er ba l in te lle ct ual a bili tie s, m em or y ( te st b at te ry) N o s ig ni fic an t d ec lin e, im pr ov ed s co re s o n pe rc ep tu al re as on in g U nk now n O ve ra ll o ra l me di ca tion re du ce d – Im pr ov em en t p ar tly du e t o r ed uc tio n i n dy st on ia , me di ca tion A cqu ire d ys to ni a ( Tar di ve d ys ki ne si a) D am ie r 20 07 [6 0] C ase se ries (10 ) Se ve re t ar di ve dy sk in es ia ; A ge 4 5 ± 5 ; D D 5 ± 1 6 M M SE < 2 4 G lo ba l c og ni tio n a nd fr on ta l f un ct ion in g (M M SE , M D RS , F A B an d F BS ) St ab le s co re s o n a ll f ou r sco re s. 62 % ** (E SR S) N o c ha ng e i n an tip syc ho tic s an d ant id ep re ss ant s G rub er 20 09 [4 3] C ase se ries (9) Ta rd iv e d ys to ni a; Ag e 6 3 ± 1 3; D D 5 ± 3 18 M D RS <1 23 G lob al c og nit io n, al er tn es s, e xe cu tiv e fu nc tio n, le ar ni ng a nd m em or y, digi t s pa n N o c ha ng es w ith o nl y a tr en d f or i m pr ov em en t i n ve rb al fl ue nc y Po uc let -C ou tr e-m anc he 20 16 [4 4] C ase se ries (19 ) Ag e 5 2 (2 5-69 ); D D 6 ( 1-38 ) 12 M M SE < 24 G lo ba l c og ni tio n a nd fr on ta l f un ct ion in g (MM SE , MDR S, F A B) St ab le M M SE a nd F A B, im pr ov em en t o n M D RS 82 % *** (B FMDR S) – Im pr ov em en t o n M D RS on s ub sc or es a tt en tio n an d c on ce pt ua liz at io n Va rio us e tio lo gi es H albi g 20 05 [42 ] C ase se ries (1 5) Id io pa th ic , i nh er ite d an d t ar di ve dys to ni a; Ag e 4 6 ( 13 -3 8) ; D D 1 3 ( 6-62 ) 7 N ot coope ra tiv e G lob al c og nit io n, al er tn es s, a tt en tio n a nd ex ec ut iv e f un ct io ns , le ar ni ng a nd m em or y (te st b at te ry ) Im pr ov em en t o n t ra il-m ak in g t es t, l ike ly d ue t o im pr ov em en t i n m ot or fu nc tio n. O th er c og ni tiv e m ea su re s s ta bl e o r n on -si gn ifi ca nt ly i m pr ov ed . 71% *** (B FMDR S) Re duct ion or ce ss at io n o f ant id ys to ni c m ed ic at io n i n 10/ 15 p at ie nt s – Re ac tio n t im es in cr ea se d i n s ta bl e m ed ic at io n pa tie nt s, bu t n ot s ig ni fic an tly
Au th or D es ig n ( n) D ia gn os is ; a ge an d; di se as e dura tio n (D D) i n y ea rs Fo llo w -up i n mo nt h Ex cl us io n cr ite ri a C og ni tiv e f un ct io n (me as ur e) C og ni tiv e o ut co m e M ea n % of m ot or imp ro ve m ent C ha ng e i n m ed ic at io n Re m ar ks D e G us m ao 20 17 [8 9] C ase se ries (12 ) Fo ca l, s eg m en ta l an d g en er al iz ed dy st on ia o f in he rit ed , i di op at hi c an d t ar di ve ; A ge 42 .3 ; D D 1 0. 1 13 N ot a n in ta ct cog nit io n C og ni tio n; a tt en tio n, W M a nd p ro ce ss in g sp ee d; lan gu ag e; v isu o-sp at ia l f un ct io n a nd me mor y O ve ra ll s ta bl e, i m pr ov ed w or ki ng me mor y ( le tt er -nu m be r s eq ue nc in g ( 17 .1 ± 4 .4 v s 1 8. 8 ± 4 .1 *) a nd co gn iti ve s et s hi ft in g (tr ai ls B 80 .6 ± 34 .7 vs 70 .4 ± 3 3. 3 *) 61% 1 O ra l m ed ic at io n in cr ea se d (1 ), s ta bl e ( 3) , re du ce d ( 6) o r st op pe d ( 2) – No co rr el at io n be tw ee n m ot or a nd c og ni tiv e ou tcom e – N o d et ai ls r eg ar di ng po ss ib le e ff ec t o f ch an ge i n m ed ic at io n an d co gn iti ve o ut com e Te st b at te ry w as u se d i f t he re w er e m or e t ha n fi ve m ea su re s u se d i n o ne s tu dy . F AB , f ro nt al a ss es sm en t b at te ry ; F BS f ro nt ot em po ra l b eh av io ra l s ca le ; I Q , I nt el lig en ce q uo tie nt ; M D RS , M at tis D em en tia R at in g S ca le ; M M SE , M in i M en ta l S ta te E xa m in at io n; B PV S, B rit is h P ic tu re V oc ab ul ar y S ca le ; W IS C , W ec hs le r I nt el lig en ce S ca le f or C hi ld re n; B FM D RS -M , Bu rk e-Fa hn -M ar sd en d ys to ni a r at in g s ca le m ot or s ub sc al e ( 0-12 0) ; E SR S, E xt ra py ra m id al S ym pt om R at in g S ca le ; T W ST RS -S , T or on to W es te rn S pa sm od ic T or tic ol lis R at in g Sc al e s ev er ity s ub sc al e ( 0-35 ); P K AN , P an to th en at e k in as e-as so ci at ed n eu ro de ge ne ra tio n; ns no n-si gn ifi ca nt ; * p ≤0 .0 5; * * p ≤0 .0 1; * ** p≤ 0. 00 1
