Longterm Deep Brain Stimulation withdrawal: Clinical stability despite physiological instability Diane Ruge, Laura Cif, Patricia Limousin, Victoria Gonzalez, Xavier Vasques, Philippe Coubes, John C. Rothwell PII: DOI: Reference:
S0022-510X(14)00301-3 doi: 10.1016/j.jns.2014.05.011 JNS 13188
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
24 March 2014 3 May 2014 6 May 2014
Please cite this article as: Ruge Diane, Cif Laura, Limousin Patricia, Gonzalez Victoria, Vasques Xavier, Coubes Philippe, Rothwell John C., Longterm Deep Brain Stimulation withdrawal: Clinical stability despite physiological instability, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Longterm Deep Brain Stimulation withdrawal:
T
Clinical stability despite physiological instability
IP
† Diane Ruge *a MD, Laura Cif *b-f MD, Patricia Limousin aMD, Victoria Gonzalezb-f
Sobell Department of Motor Neuroscience and Movement Disorders, UCL-institute of Neurology, University College London, 33 Queen Square, London WC1N3BG, United Kingdom
NU
a)
SC R
MD, Xavier Vasques gPhD, Philippe Coubes b-fMD, and John C. Rothwell a PhD
b) CHRU Montpellier, Hôpital Gui de Chauliac, Département de Neurochirurgie, Montpellier, F-34000 France; c)
MA
Unité de Recherche sur les Mouvements Anormaux, URMA; d) INSERM, U661, Montpellier, F-34000 France; e) Université de Montpellier 1, Montpellier, F-34000 France ; f) CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, F-34000 France ; g) IBM
Correspondence to: Dr. Ruge, as above, email: [email protected],
CE P
†
TE
D
*Drs . Ruge and Cif are shared first authors
telephone +44 (0)2 0 0845 155 5000, fax +44 (0)20 7278 9836
AC
Running title: Physiology of long term DBS withdrawal
Key words: genetic dystonia, deep brain stimulation, withdrawal, electrophysiology, stability Figures: 1 (colour 1) Tables: 1 Word count: 1165 Word count abstract: 173 Number of characters in title: 70 Number of characters in running title: 33 Keywords: brain stimulation, dystonia, electrophygiology, human, DBS withrawal
1
T
ACCEPTED MANUSCRIPT
SC R
IP
Abstract:
Deep brain stimulation (DBS) is a powerful treatment option for movement disorders, including severe generalised dystonia. After several years of treatment, cases have been reported in which DBS has been stopped without any deterioration in clinical benefit. This
NU
might indicate that DBS can restore function in some cases. The mechanism of DBS induced clinical retention effects has been addressed before. Here, the question we asked
MA
was if such clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of
D
neurophysiological instability. We recorded patients with pre-intervention life-
TE
threatening or severe genetic dystonia with long lasting clinical benefit when turned off DBS. Despite clinical stability, our physiological studies revealed large changes in the
CE P
excitability of excitatory and inhibitory motor circuits in the cortex, which exceed normal fluctuation. This discrepancy between instability in the motor network physiology caused by removal of DBS and clinical stability alerts as it potentially indicates a risk to fail and
AC
cause symptoms to return.
Introduction: Despite the growing list of indications, we do not know whether prolonged deep brain stimulation (DBS) has lasting neurophysiological effects on the human brain. Although it is generally believed to be a reversible therapy, recent experimental and clinical data suggest that in some conditions chronic DBS may produce neural reorganization (1, 2). For example, during early stages of therapy, dystonia patients often revert back quickly to their pre-operative state when DBS is switched OFF whilst after several years of DBS the beneficial clinical effect in some patients can be retained for long periods (1). A fundamental question is whether these individuals have gained independence from DBS (perhaps via a disease modifying process) or whether, despite apparent clinical stability, there is evidence of underlying electrophysiological instability that might provoke a relapse at any time. This 2
ACCEPTED MANUSCRIPT is a first report on electrophysiological in relation to clinical effects of interrupting successful long term DBS for a prolonged duration of several weeks.
T
The genetic DYT1 form of dystonia has considerable phenotypic variability that ranges from
IP
asymptomatic carrier status to malignant forms that can culminate in the life threatening condition of severe status dystonicus (3-5). Pallidal deep brain stimulation (DBS) has been
SC R
used as a last resort to resolve the most severe forms including an acute dystonic storm (6). Methods: Previous studies on the DBS-mechanism in dystonia have shown that
NU
pathophysiological hallmarks of the disorder improve after starting DBS at the same time as clinical effects build-up. GABAa-receptor dependent inhibition normalises at a similar rate as
MA
disease symptoms improve; other measures, related to synaptic plasticity (long-termpotentiation-like or LTP) have a more complex, non-monotonic, time course. Despite these
D
variations, they all reach a normalized state after several months of therapeutic DBS (7).
TE
We identified three dystonia patients on the basis of their retention pattern in a previously described cohort of 10 patients (2)) who retained complete clinical benefit for long time
CE P
periods after stopping DBS (see Fig 1). Ethical approval was gained. Informed written consent was taken.
This is by no means trivial and weeks of retained clinical benefit in a severe to life
AC
threatening genetic condition is highly remarkable. All these patients were severely disabled before surgery by the genetic DYT1 dystonia. One presented with the most extreme manifestation, a dystonic storm, one other had a postural dystonia with severe truncal torsion. When we stopped their DBS-therapy for several weeks, none of these patients deteriorated clinically. For ethical reasons (two had to return to their home country where DBS was not commonly available; one patient was off DBS for >1yr without showing deterioration) their DBS-implant had to be switched on again after completion of the study. While they were on long term DBS-treatment, patients (1 female, mean age [17+2.5 years], stimulation time [6.3+1.3 years], disease duration at study date [9.3+3.3 years], mean presurgery Burke-Fahn-Marsden-dystonia (BFM)-score [72.6+8.6]) were treated with bilateral
3
ACCEPTED MANUSCRIPT internal globus pallidus DBS (pulse width [450µsec], frequency [130Hz]. The patient characteristics are summarized in Table 1.
T
During the weeks where DBS remained switched OFF, concurrent transcranial magnetic
IP
stimulation (TMS) was used to track the time course of electrophysiological markers of
SC R
dystonia and a non-specific (i.e. normal in dystonia) electrophysiological marker. Amongst the markers, SICI (short interval intracortical inhibition) is a form of GABAa-ergic inhibition whereas PAS25-effects (paired associative stimulation) may involve early stages of synaptic long term potentiation. ICF (intracortical facilitation) involves glutamatergic facilitation. For
NU
details of methods see (2, 7, 8) and figure legend. While the mechanism of DBS induced retention effects has been addressed before (7, 8), the question we asked here was if the
MA
clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of neurophysiological
D
instability. Since it has been shown repeatedly that a premature arrest of DBS can lead to
TE
life threatening complications, this is an important question to be answered. There is no neurophysiological insight into such incidents so far.
CE P
The results demonstrate that while the clinical state of the patients did not change/deteriorate when DBS was OFF for several weeks, considerable fluctuations at the neurophysiological level over the same period occurred (see Fig 1A-D). The inter-session
AC
variability exceeded that usually seen in healthy individuals (average intersession variability ~ 20% for PAS-effects as example versus ~ 100% for patients reported here) and also differed from the typical pattern in DBS naïve dystonia (7, 9). As noted above, we do not know for how long it is possible to maintain clinical benefit in such patients. It remains possible that such effect is permanent. The instability of the underlying neurophysiology is abnormal and suggests that this may not be the case. Despite the lack of clinical change, all three measures fluctuated more than expected from our previous experience in DYT1 dystonia, consistent with ongoing subclinical changes in the motor system.
4
ACCEPTED MANUSCRIPT With small sample sizes, detection of a reliable patterns to the changes in physiology is difficult. While direction and degree of changes were inconsistent between patients, obvious was the DBS-withdrawal induced large intersession variability that is usually not
T
observed. Of the parameters measured, SICI seemed to show least change over the period
IP
of withdrawal, which would be consistent with our previous findings that after implantation
SC R
DBS normalises SICI with the same time course as clinical recovery. Symptoms of our patients did not change over the three weeks, in parallel the level of SICI remained within normal range. PAS25 induced plasticity and ICF changed more than normal. In our experience such large inter-session differences do not occur, particularly for ICF, which as
NU
mentioned above is not reported to be abnormal, and suggest that they were a direct result
MA
of stopping DBS.
We hypothesise that lack of clinical change, in the face of rapidly changing underlying physiology, can be understood in terms of stability of a complex network. After years of
D
DBS, the network has achieved a highly stable state that is resistant to deviations in
TE
individual physiological measures. Thus, when DBS is stopped it takes time for the network to regain a new stable state. The unusual changes in the excitability that we observed reflect
CE P
instability of the network as it seeks equilibrium. As the network develops into this new state, clinical changes would become apparent. Hysteresis (the “lagging behind”) in the time course of clinical effects following DBS thus might reflect the time taken for the motor
AC
system to find a new equilibrium after sudden introduction or removal of chronic high frequency stimulation. If this is correct, it is important to consider for how long clinically stable patients can be left OFF DBS without risk of provoking a cascade of clinical deterioration. In conclusion, it is highly remarkable that individual patients suffering from a severe genetic condition, such as DYT 1 dystonia, who have been on effective long term deep brain stimulation gained a window of symptom relief without DBS-treatment. Importantly, the clinical stability does not find a correlate in the underlying physiology. The physiological instability despite clinical stability might imply that this is a transient state. If correct this has consequences for clinical practice as enduring clinical stability cannot be taken for granted and such patients should be closely monitored. 5
ACCEPTED MANUSCRIPT
5.
6. 7.
8.
IP
SC R
NU
AC
9.
MA
4.
D
3.
TE
2.
Hebb MO, Chiasson P, Lang AE, Brownstone RM, Mendez I. Sustained relief of dystonia following cessation of deep brain stimulation. Mov Disord. 2007;22(13):1958-62. Ruge D, Cif L, Limousin P, Gonzalez V, Vasques X, Hariz MI, et al. Shaping reversibility? Longterm deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms. Brain. 2011;134(Pt 7):2106-15. Opal P, Tintner R, Jankovic J, Leung J, Breakefield XO, Friedman J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm. Mov Disord. 2002;17(2):339-45. Nomura Y, Ikeuchi T, Tsuji S, Segawa M. Two phenotypes and anticipation observed in Japanese cases with early onset torsion dystonia (DYT1) - pathophysiological consideration. Brain Dev. 2000;22 Suppl 1:S92-101. Bentivoglio AR, Loi M, Valente EM, Ialongo T, Tonali P, Albanese A. Phenotypic variability of DYT1-PTD: does the clinical spectrum include psychogenic dystonia? Mov Disord. 2002;17(5):1058-63. Elkay M, Silver K, Penn RD, Dalvi A. Dystonic storm due to Batten's disease treated with pallidotomy and deep brain stimulation. Mov Disord. 2009;24(7):1048-53. Ruge D, Tisch S, Hariz MI, Zrinzo L, Bhatia KP, Quinn NP, et al. Deep brain stimulation effects in dystonia: Time course of electrophysiological changes in early treatment. Mov Disord. 2011. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol. 1993;471:501-19. Quartarone A, Rizzo V, Terranova C, Morgante F, Schneider S, Ibrahim N, et al. Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia. Brain. 2009;132(Pt 10):2871-7.
CE P
1.
T
References
Acknowledgement: DR was supported by the “The Dorothy Feiss Scientific Research Grant”, DR and JCR were supported by the Tourette Syndrome Association. LC received honoraria from Medtronic. JCR was supported by a FP7 grant from the European Union (“PLASTICISE”). PL was supported by the Parkinson’s Appeal. PL received honoraria from Medtronic and St. Jude for lectures.
6
ACCEPTED MANUSCRIPT Figure legend:
NU
SC R
IP
T
A: CHANGE OF INTRACORTICAL EXCITABILITY. A shows the results for a standard paired pulse paradigm, for methods see (4)). The x-axis represents interstimulus intervals (ISI). The red circle marks ISI 2 and 3ms and represents “short latency intracortical inhibition” (GABAa-receptor related activity). The results of this are extracted and averaged in B. In A the blue circle marks ISI 10, 12 and 15ms and represents “intracortical facilitation” (glutamatergic function). These data are extracted and averaged in C. The y-axes in A,B and C represent the ratio of a conditioned and a single TMS-pulse (for methods see (4)). Therefore, a value below 100% represents inhibition, above 100% facilitation. The x-axes in B,C,D represent the time course of recordings (ON, 2 days OFF, >14OFF) and individual patients (pat1, pat2, pat3). B: All patients showed trends but no change in SICI (GABAarelated inhibition). C: ICF (glutamatergic) function changed when patients were switched
D
MA
OFF (paired t-test for “ON” versus “OFF>14d”: t=2.14; p100% indicates LTP-like plasticity. In two patients
CE P
TE
this measure changed significantly (pat1: ON versus OFF2, paired t-test: t=-6.08; p 14 d OFF DBS
14
13
5.5
DBS withdrawal (years)
n.a. (ethical reason)
1
n.a. (ethical reason)
BFM 1 year OFF DBS
n.a.
13
n.a.
TE
AC
NU
D
MA
4.5
CE P
BFM ON-DBS
1
9
ACCEPTED MANUSCRIPT Highlights DBS can produce prolonged clinical relief outlasting stimulation. This can be the case in a life threatening genetic condition.
IP
T
Despite clinical stability electrophysiological instability occurs when DBS is stopped.
AC
CE P
TE
D
MA
NU
This should alert clinicians to perform close follow-ups.
SC R
Clinic/electrophysiology discrepancy might indicate temporary stability.
10
S0022-510X(14)00301-3 doi: 10.1016/j.jns.2014.05.011 JNS 13188
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
24 March 2014 3 May 2014 6 May 2014
Please cite this article as: Ruge Diane, Cif Laura, Limousin Patricia, Gonzalez Victoria, Vasques Xavier, Coubes Philippe, Rothwell John C., Longterm Deep Brain Stimulation withdrawal: Clinical stability despite physiological instability, Journal of the Neurological Sciences (2014), doi: 10.1016/j.jns.2014.05.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Longterm Deep Brain Stimulation withdrawal:
T
Clinical stability despite physiological instability
IP
† Diane Ruge *a MD, Laura Cif *b-f MD, Patricia Limousin aMD, Victoria Gonzalezb-f
Sobell Department of Motor Neuroscience and Movement Disorders, UCL-institute of Neurology, University College London, 33 Queen Square, London WC1N3BG, United Kingdom
NU
a)
SC R
MD, Xavier Vasques gPhD, Philippe Coubes b-fMD, and John C. Rothwell a PhD
b) CHRU Montpellier, Hôpital Gui de Chauliac, Département de Neurochirurgie, Montpellier, F-34000 France; c)
MA
Unité de Recherche sur les Mouvements Anormaux, URMA; d) INSERM, U661, Montpellier, F-34000 France; e) Université de Montpellier 1, Montpellier, F-34000 France ; f) CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, F-34000 France ; g) IBM
Correspondence to: Dr. Ruge, as above, email: [email protected],
CE P
†
TE
D
*Drs . Ruge and Cif are shared first authors
telephone +44 (0)2 0 0845 155 5000, fax +44 (0)20 7278 9836
AC
Running title: Physiology of long term DBS withdrawal
Key words: genetic dystonia, deep brain stimulation, withdrawal, electrophysiology, stability Figures: 1 (colour 1) Tables: 1 Word count: 1165 Word count abstract: 173 Number of characters in title: 70 Number of characters in running title: 33 Keywords: brain stimulation, dystonia, electrophygiology, human, DBS withrawal
1
T
ACCEPTED MANUSCRIPT
SC R
IP
Abstract:
Deep brain stimulation (DBS) is a powerful treatment option for movement disorders, including severe generalised dystonia. After several years of treatment, cases have been reported in which DBS has been stopped without any deterioration in clinical benefit. This
NU
might indicate that DBS can restore function in some cases. The mechanism of DBS induced clinical retention effects has been addressed before. Here, the question we asked
MA
was if such clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of
D
neurophysiological instability. We recorded patients with pre-intervention life-
TE
threatening or severe genetic dystonia with long lasting clinical benefit when turned off DBS. Despite clinical stability, our physiological studies revealed large changes in the
CE P
excitability of excitatory and inhibitory motor circuits in the cortex, which exceed normal fluctuation. This discrepancy between instability in the motor network physiology caused by removal of DBS and clinical stability alerts as it potentially indicates a risk to fail and
AC
cause symptoms to return.
Introduction: Despite the growing list of indications, we do not know whether prolonged deep brain stimulation (DBS) has lasting neurophysiological effects on the human brain. Although it is generally believed to be a reversible therapy, recent experimental and clinical data suggest that in some conditions chronic DBS may produce neural reorganization (1, 2). For example, during early stages of therapy, dystonia patients often revert back quickly to their pre-operative state when DBS is switched OFF whilst after several years of DBS the beneficial clinical effect in some patients can be retained for long periods (1). A fundamental question is whether these individuals have gained independence from DBS (perhaps via a disease modifying process) or whether, despite apparent clinical stability, there is evidence of underlying electrophysiological instability that might provoke a relapse at any time. This 2
ACCEPTED MANUSCRIPT is a first report on electrophysiological in relation to clinical effects of interrupting successful long term DBS for a prolonged duration of several weeks.
T
The genetic DYT1 form of dystonia has considerable phenotypic variability that ranges from
IP
asymptomatic carrier status to malignant forms that can culminate in the life threatening condition of severe status dystonicus (3-5). Pallidal deep brain stimulation (DBS) has been
SC R
used as a last resort to resolve the most severe forms including an acute dystonic storm (6). Methods: Previous studies on the DBS-mechanism in dystonia have shown that
NU
pathophysiological hallmarks of the disorder improve after starting DBS at the same time as clinical effects build-up. GABAa-receptor dependent inhibition normalises at a similar rate as
MA
disease symptoms improve; other measures, related to synaptic plasticity (long-termpotentiation-like or LTP) have a more complex, non-monotonic, time course. Despite these
D
variations, they all reach a normalized state after several months of therapeutic DBS (7).
TE
We identified three dystonia patients on the basis of their retention pattern in a previously described cohort of 10 patients (2)) who retained complete clinical benefit for long time
CE P
periods after stopping DBS (see Fig 1). Ethical approval was gained. Informed written consent was taken.
This is by no means trivial and weeks of retained clinical benefit in a severe to life
AC
threatening genetic condition is highly remarkable. All these patients were severely disabled before surgery by the genetic DYT1 dystonia. One presented with the most extreme manifestation, a dystonic storm, one other had a postural dystonia with severe truncal torsion. When we stopped their DBS-therapy for several weeks, none of these patients deteriorated clinically. For ethical reasons (two had to return to their home country where DBS was not commonly available; one patient was off DBS for >1yr without showing deterioration) their DBS-implant had to be switched on again after completion of the study. While they were on long term DBS-treatment, patients (1 female, mean age [17+2.5 years], stimulation time [6.3+1.3 years], disease duration at study date [9.3+3.3 years], mean presurgery Burke-Fahn-Marsden-dystonia (BFM)-score [72.6+8.6]) were treated with bilateral
3
ACCEPTED MANUSCRIPT internal globus pallidus DBS (pulse width [450µsec], frequency [130Hz]. The patient characteristics are summarized in Table 1.
T
During the weeks where DBS remained switched OFF, concurrent transcranial magnetic
IP
stimulation (TMS) was used to track the time course of electrophysiological markers of
SC R
dystonia and a non-specific (i.e. normal in dystonia) electrophysiological marker. Amongst the markers, SICI (short interval intracortical inhibition) is a form of GABAa-ergic inhibition whereas PAS25-effects (paired associative stimulation) may involve early stages of synaptic long term potentiation. ICF (intracortical facilitation) involves glutamatergic facilitation. For
NU
details of methods see (2, 7, 8) and figure legend. While the mechanism of DBS induced retention effects has been addressed before (7, 8), the question we asked here was if the
MA
clinical stability is reflected at the underlying physiology level or whether there is indication to believe that a stand-still of symptoms might be at risk because of neurophysiological
D
instability. Since it has been shown repeatedly that a premature arrest of DBS can lead to
TE
life threatening complications, this is an important question to be answered. There is no neurophysiological insight into such incidents so far.
CE P
The results demonstrate that while the clinical state of the patients did not change/deteriorate when DBS was OFF for several weeks, considerable fluctuations at the neurophysiological level over the same period occurred (see Fig 1A-D). The inter-session
AC
variability exceeded that usually seen in healthy individuals (average intersession variability ~ 20% for PAS-effects as example versus ~ 100% for patients reported here) and also differed from the typical pattern in DBS naïve dystonia (7, 9). As noted above, we do not know for how long it is possible to maintain clinical benefit in such patients. It remains possible that such effect is permanent. The instability of the underlying neurophysiology is abnormal and suggests that this may not be the case. Despite the lack of clinical change, all three measures fluctuated more than expected from our previous experience in DYT1 dystonia, consistent with ongoing subclinical changes in the motor system.
4
ACCEPTED MANUSCRIPT With small sample sizes, detection of a reliable patterns to the changes in physiology is difficult. While direction and degree of changes were inconsistent between patients, obvious was the DBS-withdrawal induced large intersession variability that is usually not
T
observed. Of the parameters measured, SICI seemed to show least change over the period
IP
of withdrawal, which would be consistent with our previous findings that after implantation
SC R
DBS normalises SICI with the same time course as clinical recovery. Symptoms of our patients did not change over the three weeks, in parallel the level of SICI remained within normal range. PAS25 induced plasticity and ICF changed more than normal. In our experience such large inter-session differences do not occur, particularly for ICF, which as
NU
mentioned above is not reported to be abnormal, and suggest that they were a direct result
MA
of stopping DBS.
We hypothesise that lack of clinical change, in the face of rapidly changing underlying physiology, can be understood in terms of stability of a complex network. After years of
D
DBS, the network has achieved a highly stable state that is resistant to deviations in
TE
individual physiological measures. Thus, when DBS is stopped it takes time for the network to regain a new stable state. The unusual changes in the excitability that we observed reflect
CE P
instability of the network as it seeks equilibrium. As the network develops into this new state, clinical changes would become apparent. Hysteresis (the “lagging behind”) in the time course of clinical effects following DBS thus might reflect the time taken for the motor
AC
system to find a new equilibrium after sudden introduction or removal of chronic high frequency stimulation. If this is correct, it is important to consider for how long clinically stable patients can be left OFF DBS without risk of provoking a cascade of clinical deterioration. In conclusion, it is highly remarkable that individual patients suffering from a severe genetic condition, such as DYT 1 dystonia, who have been on effective long term deep brain stimulation gained a window of symptom relief without DBS-treatment. Importantly, the clinical stability does not find a correlate in the underlying physiology. The physiological instability despite clinical stability might imply that this is a transient state. If correct this has consequences for clinical practice as enduring clinical stability cannot be taken for granted and such patients should be closely monitored. 5
ACCEPTED MANUSCRIPT
5.
6. 7.
8.
IP
SC R
NU
AC
9.
MA
4.
D
3.
TE
2.
Hebb MO, Chiasson P, Lang AE, Brownstone RM, Mendez I. Sustained relief of dystonia following cessation of deep brain stimulation. Mov Disord. 2007;22(13):1958-62. Ruge D, Cif L, Limousin P, Gonzalez V, Vasques X, Hariz MI, et al. Shaping reversibility? Longterm deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms. Brain. 2011;134(Pt 7):2106-15. Opal P, Tintner R, Jankovic J, Leung J, Breakefield XO, Friedman J, et al. Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm. Mov Disord. 2002;17(2):339-45. Nomura Y, Ikeuchi T, Tsuji S, Segawa M. Two phenotypes and anticipation observed in Japanese cases with early onset torsion dystonia (DYT1) - pathophysiological consideration. Brain Dev. 2000;22 Suppl 1:S92-101. Bentivoglio AR, Loi M, Valente EM, Ialongo T, Tonali P, Albanese A. Phenotypic variability of DYT1-PTD: does the clinical spectrum include psychogenic dystonia? Mov Disord. 2002;17(5):1058-63. Elkay M, Silver K, Penn RD, Dalvi A. Dystonic storm due to Batten's disease treated with pallidotomy and deep brain stimulation. Mov Disord. 2009;24(7):1048-53. Ruge D, Tisch S, Hariz MI, Zrinzo L, Bhatia KP, Quinn NP, et al. Deep brain stimulation effects in dystonia: Time course of electrophysiological changes in early treatment. Mov Disord. 2011. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol. 1993;471:501-19. Quartarone A, Rizzo V, Terranova C, Morgante F, Schneider S, Ibrahim N, et al. Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia. Brain. 2009;132(Pt 10):2871-7.
CE P
1.
T
References
Acknowledgement: DR was supported by the “The Dorothy Feiss Scientific Research Grant”, DR and JCR were supported by the Tourette Syndrome Association. LC received honoraria from Medtronic. JCR was supported by a FP7 grant from the European Union (“PLASTICISE”). PL was supported by the Parkinson’s Appeal. PL received honoraria from Medtronic and St. Jude for lectures.
6
ACCEPTED MANUSCRIPT Figure legend:
NU
SC R
IP
T
A: CHANGE OF INTRACORTICAL EXCITABILITY. A shows the results for a standard paired pulse paradigm, for methods see (4)). The x-axis represents interstimulus intervals (ISI). The red circle marks ISI 2 and 3ms and represents “short latency intracortical inhibition” (GABAa-receptor related activity). The results of this are extracted and averaged in B. In A the blue circle marks ISI 10, 12 and 15ms and represents “intracortical facilitation” (glutamatergic function). These data are extracted and averaged in C. The y-axes in A,B and C represent the ratio of a conditioned and a single TMS-pulse (for methods see (4)). Therefore, a value below 100% represents inhibition, above 100% facilitation. The x-axes in B,C,D represent the time course of recordings (ON, 2 days OFF, >14OFF) and individual patients (pat1, pat2, pat3). B: All patients showed trends but no change in SICI (GABAarelated inhibition). C: ICF (glutamatergic) function changed when patients were switched
D
MA
OFF (paired t-test for “ON” versus “OFF>14d”: t=2.14; p100% indicates LTP-like plasticity. In two patients
CE P
TE
this measure changed significantly (pat1: ON versus OFF2, paired t-test: t=-6.08; p 14 d OFF DBS
14
13
5.5
DBS withdrawal (years)
n.a. (ethical reason)
1
n.a. (ethical reason)
BFM 1 year OFF DBS
n.a.
13
n.a.
TE
AC
NU
D
MA
4.5
CE P
BFM ON-DBS
1
9
ACCEPTED MANUSCRIPT Highlights DBS can produce prolonged clinical relief outlasting stimulation. This can be the case in a life threatening genetic condition.
IP
T
Despite clinical stability electrophysiological instability occurs when DBS is stopped.
AC
CE P
TE
D
MA
NU
This should alert clinicians to perform close follow-ups.
SC R
Clinic/electrophysiology discrepancy might indicate temporary stability.
10
