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Reduction in DBS frequency improves balance difficulties after thalamic DBS for essential tremor
Journal of the Neurological Sciences 367 (2016) 122–127
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Reduction in DBS frequency improves balance difficulties after thalamic DBS for essential tremor Adolfo Ramirez-Zamora a,⁎, Hans Boggs b, Julie G. Pilitsis b a b
Department of Neurology, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, United States Department of Neurosurgery, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, United States
a r t i c l e
i n f o
Article history: Received 4 May 2015 Received in revised form 23 May 2016 Accepted 1 June 2016 Available online 2 June 2016 Keywords: Imbalance Deep brain stimulation Essential tremor Thalamus Ataxia Cerebellum
a b s t r a c t Essential tremor (ET) is a syndrome characterized by the presence of symmetric, moderate to high frequency postural and action tremors of the limbs. Additionally, increasing evidence indicates the occurrence of associated cerebellar features in ET patients including impaired gait and balance. Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been shown to be an effective treatment for medically-refractory ET tremor but its effects on balance remain unclear with conflicting results reported. In this article, we report the effects of frequency modification in four patients with disequilibrium after DBS and review available literature regarding the effects of neurostimulation on balance in ET. Reduction in DBS frequency (10–20 Hz reduction intervals) to the lowest effective settings for tremor control was conducted followed by immediate and 4-week assessment of disequilibrium. All patients reported improvement in balance ranging from mild to marked benefit on clinical global impression scale and in the posture and gait disturbance sub-scores of the International Cooperative Ataxia Rating Scale (ICARS). There was no significant difference in tremor control with DBS frequency adjustments. Our results suggest a relationship between the effects of high-frequency stimulation and disequilibrium in ET patients treated with bilateral or unilateral DBS. Additional larger, prospective studies are warranted to validate these results and discern the relationship between DBS stimulation settings and cerebellar findings in ET. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Essential tremor (ET) is one of the most common neurological disorders. Its prevalence has been estimated at 0.9% among all age groups and 4.6% for people aged 65 years and older [1]. The syndrome has been long characterized by the presence of symmetric, moderate to high frequency postural and action tremors of the limbs. With growing evidence that ET's motor pathophysiology extends beyond tremor and includes a variety of non-motor features ranging from cognitive abnormalities to psychosocial impairments, the disease's traditional classification as a monosymptomatic disorder is being reconsidered [2]. One of the most concerning symptoms now associated with ET is the occurrence of balance and gait deficits. The extent to which these deficits affect patient quality of life and mortality is unclear as this has not been a primary research focus in ET [3]. Thus, the development of potential therapies and clarification as to the relevant anatomy involved in the development of these symptoms is mostly speculative. Since early description of difficulties with tandem gait in patients with ET, a variety of dynamic and computational assessments have been conducted in ⁎ Corresponding author at: Department of Neurology, 47 New Scotland Ave, Albany, NY 12208, United States. E-mail address: [email protected] (A. Ramirez-Zamora).
http://dx.doi.org/10.1016/j.jns.2016.06.001 0022-510X/© 2016 Elsevier B.V. All rights reserved.
ET patients indicating a wide range of gait and balance difficulties [3] (Table 1). Signs of balance impairment, specifically tandem gait disturbances, have been found in both early and advanced stages of ET [4]. However, balance impairments are most readily observed in patients with advanced forms of the disease while undergoing more complicated testing conditions [3,4]. Interestingly, the balance impairment and impaired functional mobility seen in ET patients seem to be generally independent of tremor severity [4–6], though midline tremor severity subscores have been shown to correlate with increases in step width, an instability compensation strategy common in patients with cerebellar disease [5]. Further studies are needed to determine whether balance and gait impairment might be present before the onset of tremor. Chronic high frequency deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been shown to be an effective long-term treatment for medically-refractory ET tremor [7]. The effects of thalamic DBS on the gait and balance features of ET are still under investigation and are less clearly defined. Several recent reports describe modulation of tremor and cerebellar signs after altering DBS frequency [4,7–11] (Table 2). Pedrosa et al. investigated the effects of varying DBS frequency on tremor severity [8]. His group concluded that while high frequency DBS (120–150 Hz) effectively treats both postural and intentional tremor, low frequency DBS (10 Hz) exacerbated tremor symptoms, with intentional tremor amplitude being more
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Table 1 Summary of studies investigating the relationship between ET and gait and balance disorder. Author (year)
# of patients
Bove (2006)
19 ET (12, arms only; 7, +head) 19 healthy controls Parisi (2006) 16 ET w/ head tremor 14 ET w/o head tremor 28 healthy controls Kronenbuerger 25 ET (18 w/ (2009) postural/kinetic tremor; 7 w/ cerebellar signs) 25 healthy controls Hoskovcova 30 ET (2012) 25 healthy controls
Experimental design
Results
Static posturography with eyes open and closed during quiet stance and performance of mental or motor task; center of foot pressure and postural sway measured Subjects assessed using functional mobility performance and self-report measures (Timed Up & Go; Dynamic Gait Index; Berg Balance Scale; etc.) Balance control measured by tandem treadmill gait & static and dynamic posturography
Balance control is only minimally affected in ET; patients with head involvement and longer disease duration tend to present a reduced postural stability Subjects with ET showed reduced functional mobility, especially those with head tremor
Subjects underwent posturography and gait assessment; assessment via ABC, FAB, ICARS scales; tremor evaluation via rating scale and accelerometry
ET patients showed increased number of missteps, shortened stride length w/ tandem gait; both ET groups had increased postural instability in dynamic posturography – more so in ET subjects w/ cerebellar signs. Confirms ET is associated with cerebellar impairment. ET subjects exhibited: lower tandem gait velocity; more missteps; increased postural sway. Step width in normal gait of ET subjects increased w/ midline tremor subscore of TRS. Significant correlations found between age and quantitative measures of gait.
ABC = Activities-Specific Balance Confidence. FAB = Fullerton Advanced Balance. ICARS = International Cooperative Ataxia Rating Scale. TRS = tremor rating scale.
strongly affected compared to postural tremor. As intentional tremor has been attributed to a greater extent to cerebellar dysfunction, the author's findings imply the possibility of two separate mechanisms underlying the two tremor entities. Fasano et al. reported that therapeutic DBS intensity levels suppress both tremor and cerebellar dysfunction,
while supra-therapeutic stimulation (defined by increasing the amplitude and pulse width until decomposition of movement in the finger to nose test) extinguishes tremor and results in the return of cerebellar dysfunction, implying that the variation of DBS intensity may affect two different circuits: the cortico-thalamo-cortical loop for tremor reduction
Table 2 Summary of studies investigating the effects of DBS on gait and balance in ET. Author (year)
# of patients
Experimental design
DBS settings
Ondo (2006)
13 ET w/ VIM DBS
Computerized posturography
DBS-on DBS-off
Pahwa (2006)
26 ET w/ VIM DBS (18, unilateral; 8, bilateral) 13 ET w/ bilateral VIM DBS
Earhart (2009)
Fasano (2009)
11 ET w/ thalamic DBS
Kronenbuerger 12 ET w/ (2009) thalamic DBS
Hwynn (2011)
38 ET (25 w/ unilateral; 13 w/ bilateral VIM DBS)
Pedrosa (2013)
16 ET w/ bilateral thalamic DBS
Results
With DBS-on, ET subjects showed significant improvement over trials on dorsiflexion texts. No such adaptation over trials was shown with DBS-off. Falls lessened with DBS-on in ET subjects. Bilateral VIM DBS mostly improved balance, but may worsen other specific features. Evaluated using Fahn-Tolosa-Marin tremor rating scale DBS-on In ET patients receiving bilateral stimulation, 25% experienced DBS-off balance difficulties. Disequilibrium, balance difficulties, and abnormal gait were more common in bilateral ET subjects than in unilateral. Standard and tandem walking; Berg Balance Score, DBS-on Compared to controls, subjects w/ ET walked significantly Balance confidence, Timed Up-and-Go DBS-off more slowly for both standard and tandem walking, spent lower percentage of gait cycle in single limb support, higher percentage in double support, lower Berg balance scores, greater time to perform Timed Up-and-Go. No significant differences in any gait or balance measure for DBS-on vs. DBS-off. However, effects of DBS on gait and balance were highly variable between individuals. Locomotion assessed via: overground gait and tandem DBS-on During DBS-off, subjects exhibited ataxia in all assessments, gait; balance-assisted treadmill tandem gait; DBS-off which improved during DBS-on and worsened again during unassisted treadmill gait Supratherapeutic supratherapeutic stimulation. These improvements in ataxia were not a function of reduced tremor in lower limbs or torso. Balance control measured by tandem treadmill gait & DBS-on DBS of ventrolateral thalamus did not significantly affect static and dynamic posturography DBS-off balance control, as measured via performance in tandem gait or posturography; ET patients with and without clinical cerebellar impairment showed increased postural instability; confirms that ET is associated with cerebellar impairment. Retrospective chart review; FTM TRS & individual No stimulation 21% of full cohort experienced worsened gait with falls upper extremity scores. Recorded at: baseline, setting variation; post-DBS. Baseline pre-morbid gait difficulty varied: 61% in 6-months post-unilateral/6–12 months post-bilateral Evaluations pre- unilateral cases; 46% in bilateral cases. Post-op gait worsening surgery. and post-DBS associated with more severe disease; older age (weak Further categorized by baseline and post-DBS gait correlation); & pre-op balance difficulty, especially w/ difficulties: −gait pre/−gait post; −gait pre/+gait bilateral surgery. Higher baseline TRS associated with post-op post; +gait pre/++gait post; +gait pre/−+gait post gait worsening. Tremor rating scale and ultrasound-based tremor HFS HFS successfully treats tremor; LFS increases tremor amplitude measurements LFS (10 Hz) compared with DBS-off; more severe effect of LFS on DBS-off intentional tremor compared with postural tremor – implying different mechanisms responsible for both types of tremor
HFS = high frequency (deep brain) stimulation. LFS = low frequency (deep brain) stimulation. DBS-on = deep brain stimulation on. DBS-off = deep brain stimulation off. Supratherapeutic = defined by increasing amplitude and pulse width until exposure of cerebellar dysfunction is apparent.
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and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation) [9]. Impaired gait has been conventionally held as a potential adverse effect of bilateral DBS with reports ranging from 26% to 55% [7,12]. Management of imbalance can be challenging, as reduction in stimulation parameters commonly leads to tremor recurrence or no effect on disequilibrium. However, others have presented contradictory evidence showing that DBS has no adverse effect on gait and balance in unilateral and bilateral stimulation [4,11] and even a positive effect on symptoms dependent on the mode of stimulation [9,10]. Although thalamic DBS is a safe and effective treatment for medically refractory ET, increasing reports suggest that the posterior subthalamic area might be a more efficient target [13,14]. Nevertheless, both targets required HFS for therapeutic purposes with frequencies typically ranging between 160 and 180 Hz. Increased frequencies commonly translate in additional tremor improvement, although systematic analysis of specific programming parameters modifications are lacking. It is thought that thalamic DBS exerts its effects through modulation of cerebellothalamo-cortical connections by changing the pattern of neuronal activity [15]. Because of the occurrence of a possible U-shaped correlation between stimulation strength and cerebellar findings couple with potential exacerbation of cerebellar findings with supratherapeutic stimulation levels, we aimed to assess the efficacy of reduction of DBS frequency in patients complaining of worsening balance after HFS thalamic DBS. In this report, we present the effects of DBS frequency variation on tremor control and disequilibrium in a cohort of 4 ET patients presenting with worsening disequilibrium and ataxia following treatment with thalamic DBS. Additionally, we present a review of recent literature regarding the topic. 2. Methods We performed a PubMed search using different combinations between the terms ‘imbalance,’ ‘disequilibrium,’ ‘falls’, ‘unsteadiness’ and ‘Deep Brain Stimulation/DBS’. The respective medical subheading in the search strategy was included when available. Relevant case reports, case series and studies that were published in peer-reviewed journals and available in full text and written in English were included in our review (Table 2). All participants were diagnosed with essential tremor according to the criteria of the consensus statement of the Movement Disorder Society Group [16]. Albany Medical College institutional review board approved the study. Informed consent was obtained from all patients after reviewing study protocol. Patients were recruited and identified during routine outpatient clinic follow up from June 2013 to August 2014. Patients with unilateral or bilateral thalamic VIM DBS were considered. A semi-structured interview screening for balance difficulties was conducted by the treating neurologist (ARZ). Key inclusion criteria for participation in the study included 1) subjective reports of worsening balance after surgery, 2) diagnosis of ET based on Movement Disorder Society guidelines refractory to medical treatment, 3) disease duration N10 years, and 4) stable dose of medications for tremor at least one
month prior to intervention and during study duration. Key exclusion criteria included 1) the presence of secondary factors leading to imbalance including weakness, musculoskeletal problems, vestibular dysfunction, visual impairment, or severe proprioceptive deficits, 2) untreated or clinically significant depression or psychiatric disease, 3) marked cognitive impairment and 4) other significant conditions that could interfere with assessments or participation. A total of 12 patients were identified during the screening period but 8 patients were excluded because of the presence of additional causes of disequilibrium (6) and denial of participation in the study (2). Other overt causes of imbalance in these patients included the presence of peripheral neuropathy with sensory ataxia due to Diabetes Mellitus (2) or idiopathic (1), associated parkinsonism due to exposure to dopamine blocking agents leading to postural instability (1) and severe knees osteoarthritis and lumbar spine disease affecting ambulation and equilibrium (2). DBS programming settings varied among patients based on tremor response and adverse effects but all patients were consistently programmed using HFS (170–185 Hz). Four patients with longstanding ET syndrome treated with thalamic DBS for medically-refractory ET with worsening equilibrium after surgery were identified (Table 3). DBS settings remained unchanged for at least three months prior to enrolling in the study. All patients reported the occurrence of worsening balance at different time points after surgery ranging from six to nineteen months. Unsteadiness was characterized by a feeling of disequilibrium or imbalance that lead to occasional falls and common near falls. Worsening elements of cerebellar ataxia during ambulation were noted on examination. A comprehensive neurological examination was conducted to exclude DBS malfunction or other causes of worsening balance and gait as described in inclusion requirements. Two patients had dominant hand, unilateral, left thalamic DBS and two patients underwent sequential, bilateral procedures. No severe gait difficulties were apparent before surgery, although mild tandem dystaxia was noted in all patients prior to DBS. Tremor control was assessed pre-operatively and at follow up using the Fahn-Tolosa-Marin (FTM) tremor rating scale. We utilized a lateralized FTM scale in patients with unilateral surgery. Ataxia and imbalance were assessed using the International Cooperative Ataxia Rating Scale (ICARS, posture and gait disturbance sub-scores) along with an unstructured, subject-completed clinical global impression scale (CGI) at 4 weeks after DBS programming changes. CGI scale ranges from 1 to 7, 1 indicating very much improved, 7 indicating very much worse compared with baseline. 3. Procedures First, all patients had stereotactic placement of unilateral or bilateral Thalamic VIM DBS electrodes as previously described [17]. Briefly, the DBS procedure was conducted utilizing the Leksell stereotactic frame. Targeting was performed using a combination of AC-PC coordinates and adjustments based on direct imaging relative to MRI visible structures along with microelectrode recordings to define the borders of VIM and sensory thalamus. Adequate final postoperative electrode
Table 3 Patient's demographics. Patient No.
Age of ET diagnosis (years)
Sex
Age at time of VIM DBS surgery (years)
Time to report imbalance after DBS (months)
1 2 3
52 21 32
Female Male Male
9 months 14 months 19 months after right VIM
4
40
Male
Mean
36.25
Standard deviation
13.07
68 (unilateral left) 44 (unilateral left) 58 (left VIM) 59 (right VIM) 66 (left VIM) 73 (right VIM) L: 59 R: 66 L: 10.89 R: 9.90 L: 4 R: 2
N
4
6 months after right VIM
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Table 4 patient's programming settings, tremor and ICARS scores. Patient
FTM tremor scale after maximized tremor control?
1
3
2
9
3
15
4
5
Programming settings for best tremor control, amplitude/pulse width/frequency
ICARS ICARS subscores subscores after DBS frequency adjustments
Programming settings for improvement in balance, amplitude/pulse width/frequency
CGI-S scale improvement at 4 weeks
Percentage Change in ICARS subscores
Contact 1 negative, 2 positive, 2.1/90/185 Contact 3 negative, contact 2 positive, 2.6/90/185. Right VIM contact 2 negative, 1 positive, 2.0/90/170. Left VIM contact 0 positive, 1 negative, 2 negative, 4.1/60/170. Left VIM contact 2 positive, 1 negative, 2.7/60/185.
5
3
2
40%
8
5
8
6
6
4
Contact 1 negative, contact 2 positive, 2.1/90/130. Contact 3 negative, 2 positive, 2.1/90/130. Right VIM contact 2 negative, 1 positive, 2.0/90/130. Left VIM contact 0 positive, 1 negative, 2 negative, 4.1/60/130. Left VIM contact 2 positive, 1 negative, 2.7/60/130
Right VIM contact 5 positive, 4 negative, 3.1/60/185. Mean Standard deviation
8 5.29
1 2
2
37.5% 25%
33.3%
Right VIM contact 5 positive, 4 negative, 3.1/60/130 6.75 1.5
4.50 1.29
33.95%
Fahn-Tolosa-Marin (FTM) tremor rating scale. International Cooperative Ataxia Rating Scale (ICARS).
locations were confirmed utilizing volumetric CT scanning registered to the preoperative Brain MRI using BrainLab (https://www.brainlab.com/ ). Patients underwent DBS programming for maximal tremor control over the following months. Once disequilibrium was reported, changes in stimulation amplitude utilizing ventral contacts did not improve or worsened disequilibrium and caused other side effects (dysarthria or paresthesia) and activation of more dorsal electrodes compromised tremor control. Reduction in voltage in unipolar mode leads to worsening tremors. Interestingly, all patients were receiving unipolar stimulation at the time they reported imbalance. Although recent reports suggest that tremor progression and possible cerebellar features are related to disease progression [18], assessment of imbalance after turning stimulators off provided improvement in patient's gait difficulties supporting the role of neurostimulation to their disequilibrium. In patients with bilateral procedures, no difference in equilibrium was noted turning either left or right hemisphere stimulators but improvement in balance was observed when both stimulators were turned off. Patients reported improvement in balance within an hour after being off stimulation. In patients with bilateral DBS, programming sessions were aimed to maximize tremor benefit with reduction in potential side effects commonly seen with bilateral surgery, particularly dysarthria. Subjects' DBS parameters were continued at the same pulse width, voltage, and combinations of active cathodes and anodes determined to be effective. A stable clinical tremor response to thalamic DBS for at least 1 month was required before assessments. Differences in patients' individual regional anatomy, lead location, and propensity to experience side effects prompted the decision to forego standardizing DBS stimulation parameters and electrode configurations in subjects. Specific differences in programming settings among patients (primarily amplitude and pulse width (PW) in patients 3 and 4) provided the best tremor response without inducing adverse effects. A specific programming paradigm beneficial to one patient might cause partial benefit or side effects to the next one. Furthermore, controlling for the total electrical charge—determined by the product of the electrical current, pulse width, and frequency—as a way to reduce variability would have failed to ensure optimal therapeutic effect. Initially, all patients were programmed in bipolar mode using HFS between 170 and 185 Hz to minimize side effects and with adequate tremor control. Reduction in DBS frequency to the lowest setting effective for tremor control in 10– 20 Hz reduction intervals was conducted with brief washout periods as performed by other groups [19]. Tremor was assessed after every interval by monitoring changes in Archimedes' spiral and ability to drink form a cup using one hand. After monitoring for acute change in
symptoms, complete assessments including ICARS were conducted 30 min after final stimulation settings were determined. Patients were reevaluated 4 weeks later and they were instructed to monitor for changes in their symptoms. 4. Results Patients tolerated changes well without significant change in tremor control (Table 4). No acute adverse effects were noted. At 4 weeks, there was a slight worsening but no statistical difference in tremors scores after DBS frequency reduction. All patients reported subjective improvement in balance ranging from mild to marked improvement on the CGI-S. ICARS scores following DBS frequency adjustments showed significant improvement from pre-adjustment scores (p = 0.003). Reintroducing HFS caused recurrence of imbalance and worsening ICARS scores in patients one, three and four. Patient two reported clear reappearance of a sense of unsteadiness without change in ICARS. Average ICARS score improvement was 2.25 ± 0.50 points. FTM scale score for maximized tremor correlated strongly with ICARS score prior to DBS frequency adjustments (r = 0.88), although this was not statistically significant (p = 0.118) indicating that patients with worse UE tremor are more likely to have worse gait/balance difficulties. Comparing FTM scale score with ICARS score measured after adjustments showed a strong and significant correlation (r = 0.98, p = 0.024). However, the strength of this correlation might be exaggerated as an artifact of our small sample size. The average decrease in frequency of stimulation to maintain tremor control was 51.25 ± 7.5 Hz. Age and disease duration were not found to have any significant predictive value for the FTM or ICARS scales. The patient with highest FTM scale scored had the smallest improvement, but there was not a linear relationship between tremor severity at baseline and improvement in ICARS with low frequency stimulation. 5. Discussion Increasing evidence emphasizes the role of the cerebellum in ET by clinical observations such as the impairment of the blink-reflex [20], ataxia during tandem gait [21] and cognitive and affective deficits [22, 23] resembling those in the ‘cerebellar cognitive affective syndrome’. Also, in a subset of patients, impaired balance has been shown to produce increased body sway [24] and decreased functional mobility, performance and self-reported measures of stability [6]. These abnormalities are independent of tremor severity and distribution [4,
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6,24]. The impact on daily function and relationship with stimulation parameters for tremor control is not known. There is conflicting evidence regarding the effects of DBS in ET. Although the effects of different paradigms have been studied, the heterogeneous nature of ET, leads location, and variable programming strategies contribute to the documented variability of these results. Our results suggest a relationship between the effects of HFS and worsening balance in ET patients implanted with bilateral or unilateral DBS. Reduction in frequency provided improvement in balance measured using ICARS subscores. In prior studies, specific balance assessments were paired with a variety of stimulation settings, including unipolar or double unipolar stimulation, variable PWs and primarily high frequencies (mean 165 Hz). Increased stimulation charge broadens the electric field radius and changes the composition of stimulated neuronal elements leading to a narrow therapeutic threshold for gait and tremor control [25]. The ultimate electrical charge might account for changes observed in different studies where disadvantageous consequences of imbalance were noted with thalamic stimulation. Additionally, most of previous studies analyzing the effects of DBS on balance utilized an OFF and ON paradigm, not permitting to assess specific differences in stimulation contacts or programming variables. In our cohort, there was not exacerbation of tremor after frequency reduction and we did not modify other stimulation settings purposefully. It is unclear why patients complained of imbalance months or years after initial implantation but we suspect that DBS causes impaired equilibrium only after a specific and individual threshold for cerebellar dysfunction has been crossed because of disease progression. Additionally, it is possible that DBS disrupted the function and role of thalamic VIM in modulation of cerebellar or vestibular system in our patients [26]. Further research is needed to clarify this point. Additionally, all our patients received solely bipolar stimulation. Although bilateral surgery has been associated with worsening balance, other groups have reported gait and disequilibrium with unilateral cases [12]. Importantly, stimulation parameters leading to imbalance and their relationship to anatomical site of stimulation need further assessment. Fasano et al. reported that stereotactic evaluation of stimulating electrodes revealed localization of the most efficacious contacts outside the thalamus within the prelemniscal radiation [9] as previously reported by other centers [27]. The simple protocol utilized in our study limits the number of confounding DBS variables and the restriction to assess only during on/off stimulation. We acknowledge the limitations in our analysis including the small sample size and the lack of more objective measures for balance assessment including tandem treadmill gait & static and dynamic posturography. Because of these limitations, we cannot determine a specific effect of DBS laterality or effects of specific locations within the thalamus. However, the design aimed to minimize other confounding variables during DBS programming. Additional studies using dynamic testing and larger-scale prospective studies are required to validate our findings and further discern the relationship between stimulation contact location and the effects of different programming settings in cerebellar findings in ET. A control group would also be needed in order to compare progression of gait difficulties in ET cohorts not undergoing DBS implantation. Additionally, future studies would need to address baseline preoperative gait and balance dysfunction comparisons to OFF-stimulation and ON-stimulation postoperative assessments (with attention to washout effects). 6. Conclusions The recognition of balance difficulties and cerebellar features in patients with ET has expanded the spectrum of clinical features observed in the disease. The effects of unilateral or bilateral thalamic DBS on equilibrium are complex with conflicting results and variable observations seen in multiple testing settings. The heterogeneity of testing conditions makes it difficult to draw definitive conclusions or to compare different results. Because of the clinical implications associated with worsening
balance in ET patients, improved treatments to maximize tremor control and mitigate side effects after DBS are needed. Identifying patients at risk for disequilibrium along with improving our understanding of the relationship between imbalance, lead locations and stimulation parameters is critical. Our study suggests a direct relation between stimulation frequency and imbalance after DBS. Despite our study limitations, our findings provide proof of concept to consider judicious reduction of stimulation frequency after maximizing tremor control to improve disequilibrium after bilateral or unilateral thalamic DBS in ET. Larger prospective, randomized, controlled studies are warranted. Conflict of interest None. Disclosures Dr. Julie Pilitsis is a consultant for Medtronic, St. Jude and Boston Scientific and receives grant support from Jazz Pharmaceuticals, Medtronic, Boston Scientific, St. Jude and NIH 1R01CA166379. She is medical advisor for Centauri and has stock equity. There was no support for this paper from any company/institution. Dr. Ramirez-Zamora has received consultant honoraria from Teva pharmaceuticals. The Phyllis E. Dake Endowed Chair in Movement Disorders supported this study. The institution and not Dr. Ramirez-Zamora receives grant support from Medtronic and Boston Scientific. Dr. Ramirez-Zamora has participated as a site PI and/or co-I for several NIH and industry sponsored trials over the years but has not received honoraria. Boggs, Hans has no conflict of interest or financial disclosures. References [1] E.D. Louis, J.J. Ferreira, How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor, Mov. Disord. 25 (5) (2010) 534–541. [2] V. Chandran, P.K. Pal, Essential tremor: beyond the motor features, Parkinsonism Relat. Disord. 18 (5) (2012) 407–413. [3] D. Arkadir, E.D. Louis, The balance and gait disorder of essential tremor: what does this mean for patients? Ther. Adv. Neurol. Disord. 6 (4) (2013) 229–236. [4] M. Kronenbuerger, J. Konczak, W. Ziegler, P. Buderath, B. Frank, V.A. Coenen, et al., Balance and motor speech impairment in essential tremor, Cerebellum 8 (3) (2009) 389–398. [5] M. Hoskovcova, O. Ulmanova, O. Sprdlik, T. Sieger, J. Novakova, R. Jech, et al., Disorders of balance and gait in essential tremor are associated with midline tremor and age, Cerebellum 12 (1) (2013) 27–34. [6] S.L. Parisi, M.E. Heroux, E.G. Culham, K.E. Norman, Functional mobility and postural control in essential tremor, Arch. Phys. Med. Rehabil. 87 (10) (2006) 1357–1364. [7] R. Pahwa, K.E. Lyons, S.B. Wilkinson, R.K. Simpson Jr., W.G. Ondo, D. Tarsy, et al., Long-term evaluation of deep brain stimulation of the thalamus, J. Neurosurg. 104 (4) (2006) 506–512. [8] D.J. Pedrosa, M. Auth, C. Eggers, L. Timmermann, Effects of low-frequency thalamic deep brain stimulation in essential tremor patients, Exp. Neurol. 248 (2013) 205–212. [9] A. Fasano, J. Herzog, J. Raethjen, F.E. Rose, M. Muthuraman, J. Volkmann, et al., Gait ataxia in essential tremor is differentially modulated by thalamic stimulation, Brain 133 (Pt 12) (2010) 3635–3648. [10] W.G. Ondo, M. Almaguer, H. Cohen, Computerized posturography balance assessment of patients with bilateral ventralis intermedius nuclei deep brain stimulation, Mov. Disord. 21 (12) (2006) 2243–2247. [11] G.M. Earhart, B.R. Clark, S.D. Tabbal, J.S. Perlmutter, Gait and balance in essential tremor: variable effects of bilateral thalamic stimulation, Mov. Disord. 24 (3) (2009) 386–391. [12] N. Hwynn, C.J. Hass, P. Zeilman, J. Romrell, Y. Dai, S.S. Wu, et al., Steady or not following thalamic deep brain stimulation for essential tremor, J. Neurol. 258 (9) (2011) 1643–1648. [13] M.T. Barbe, L. Liebhart, M. Runge, J. Deyng, E. Florin, L. Wojtecki, et al., Deep brain stimulation of the ventral intermediate nucleus in patients with essential tremor: stimulation below intercommissural line is more efficient but equally effective as stimulation above, Exp. Neurol. 230 (1) (2011) 131–137. [14] P. Blomstedt, U. Sandvik, A. Fytagoridis, S. Tisch, The posterior subthalamic area in the treatment of movement disorders: past, present, and future, Neurosurgery 64 (6) (2009) 1029–1038 (discussion 38-42). [15] T.R. Anderson, B. Hu, K. Iremonger, Z.H. Kiss, Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation-induced tremor arrest, J. Neurosci. 26 (3) (2006) 841–850.
A. Ramirez-Zamora et al. / Journal of the Neurological Sciences 367 (2016) 122–127 [16] G. Deuschl, P. Bain, M. Brin, Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee, Mov Disord. 13 (Suppl. 3) (1998) 2–23. [17] J.G. Pilitsis, L.V. Metman, J.R. Toleikis, L.E. Hughes, S.B. Sani, R.A. Bakay, Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor, J. Neurosurg. 109 (4) (2008) 640–646. [18] C.G. Favilla, D. Ullman, A. Wagle Shukla, K.D. Foote, C.E. Jacobson, M.S. Okun, Worsening essential tremor following deep brain stimulation: disease progression versus tolerance, Brain 135 (Pt 5) (2012) 1455–1462. [19] E. Moro, R.J. Esselink, J. Xie, M. Hommel, A.L. Benabid, P. Pollak, The impact on Parkinson's disease of electrical parameter settings in STN stimulation, Neurology 59 (5) (2002) 706–713. [20] M. Kronenbuerger, M. Gerwig, B. Brol, F. Block, D. Timmann, Eyeblink conditioning is impaired in subjects with essential tremor, Brain 130 (Pt 6) (2007) 1538–1551. [21] H. Stolze, G. Petersen, J. Raethjen, R. Wenzelburger, G. Deuschl, The gait disorder of advanced essential tremor, Brain 124 (Pt 11) (2001) 2278–2286. [22] F. Bermejo-Pareja, Essential tremor–a neurodegenerative disorder associated with cognitive defects? Nat. Rev. Neurol. 7 (5) (2011) 273–282.
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[23] A.I. Troster, S.P. Woods, J.A. Fields, K.E. Lyons, R. Pahwa, C.I. Higginson, et al., Neuropsychological deficits in essential tremor: an expression of cerebello-thalamo-cortical pathophysiology? Eur. J. Neurol. 9 (2) (2002) 143–151. [24] M. Bove, L. Marinelli, L. Avanzino, R. Marchese, G. Abbruzzese, Posturographic analysis of balance control in patients with essential tremor, Mov. Disord. 21 (2) (2006) 192–198. [25] Z.H. Kiss, D.M. Mooney, L. Renaud, B. Hu, Neuronal response to local electrical stimulation in rat thalamus: physiological implications for mechanisms of deep brain stimulation, Neuroscience 113 (1) (2002) 137–143. [26] B. Baier, T. Vogt, F. Rohde, H. Cuvenhaus, J. Conrad, M. Dieterich, Deep brain stimulation of the nucleus ventralis intermedius: a thalamic site of graviceptive modulation, Brain Struct. Funct. (2015). [27] J. Herzog, W. Hamel, R. Wenzelburger, M. Potter, M.O. Pinsker, J. Bartussek, et al., Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor, Brain 130 (Pt 6) (2007) 1608–1625.
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Clinical short communication
Reduction in DBS frequency improves balance difficulties after thalamic DBS for essential tremor Adolfo Ramirez-Zamora a,⁎, Hans Boggs b, Julie G. Pilitsis b a b
Department of Neurology, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, United States Department of Neurosurgery, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, United States
a r t i c l e
i n f o
Article history: Received 4 May 2015 Received in revised form 23 May 2016 Accepted 1 June 2016 Available online 2 June 2016 Keywords: Imbalance Deep brain stimulation Essential tremor Thalamus Ataxia Cerebellum
a b s t r a c t Essential tremor (ET) is a syndrome characterized by the presence of symmetric, moderate to high frequency postural and action tremors of the limbs. Additionally, increasing evidence indicates the occurrence of associated cerebellar features in ET patients including impaired gait and balance. Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been shown to be an effective treatment for medically-refractory ET tremor but its effects on balance remain unclear with conflicting results reported. In this article, we report the effects of frequency modification in four patients with disequilibrium after DBS and review available literature regarding the effects of neurostimulation on balance in ET. Reduction in DBS frequency (10–20 Hz reduction intervals) to the lowest effective settings for tremor control was conducted followed by immediate and 4-week assessment of disequilibrium. All patients reported improvement in balance ranging from mild to marked benefit on clinical global impression scale and in the posture and gait disturbance sub-scores of the International Cooperative Ataxia Rating Scale (ICARS). There was no significant difference in tremor control with DBS frequency adjustments. Our results suggest a relationship between the effects of high-frequency stimulation and disequilibrium in ET patients treated with bilateral or unilateral DBS. Additional larger, prospective studies are warranted to validate these results and discern the relationship between DBS stimulation settings and cerebellar findings in ET. © 2016 Elsevier B.V. All rights reserved.
1. Introduction Essential tremor (ET) is one of the most common neurological disorders. Its prevalence has been estimated at 0.9% among all age groups and 4.6% for people aged 65 years and older [1]. The syndrome has been long characterized by the presence of symmetric, moderate to high frequency postural and action tremors of the limbs. With growing evidence that ET's motor pathophysiology extends beyond tremor and includes a variety of non-motor features ranging from cognitive abnormalities to psychosocial impairments, the disease's traditional classification as a monosymptomatic disorder is being reconsidered [2]. One of the most concerning symptoms now associated with ET is the occurrence of balance and gait deficits. The extent to which these deficits affect patient quality of life and mortality is unclear as this has not been a primary research focus in ET [3]. Thus, the development of potential therapies and clarification as to the relevant anatomy involved in the development of these symptoms is mostly speculative. Since early description of difficulties with tandem gait in patients with ET, a variety of dynamic and computational assessments have been conducted in ⁎ Corresponding author at: Department of Neurology, 47 New Scotland Ave, Albany, NY 12208, United States. E-mail address: [email protected] (A. Ramirez-Zamora).
http://dx.doi.org/10.1016/j.jns.2016.06.001 0022-510X/© 2016 Elsevier B.V. All rights reserved.
ET patients indicating a wide range of gait and balance difficulties [3] (Table 1). Signs of balance impairment, specifically tandem gait disturbances, have been found in both early and advanced stages of ET [4]. However, balance impairments are most readily observed in patients with advanced forms of the disease while undergoing more complicated testing conditions [3,4]. Interestingly, the balance impairment and impaired functional mobility seen in ET patients seem to be generally independent of tremor severity [4–6], though midline tremor severity subscores have been shown to correlate with increases in step width, an instability compensation strategy common in patients with cerebellar disease [5]. Further studies are needed to determine whether balance and gait impairment might be present before the onset of tremor. Chronic high frequency deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been shown to be an effective long-term treatment for medically-refractory ET tremor [7]. The effects of thalamic DBS on the gait and balance features of ET are still under investigation and are less clearly defined. Several recent reports describe modulation of tremor and cerebellar signs after altering DBS frequency [4,7–11] (Table 2). Pedrosa et al. investigated the effects of varying DBS frequency on tremor severity [8]. His group concluded that while high frequency DBS (120–150 Hz) effectively treats both postural and intentional tremor, low frequency DBS (10 Hz) exacerbated tremor symptoms, with intentional tremor amplitude being more
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Table 1 Summary of studies investigating the relationship between ET and gait and balance disorder. Author (year)
# of patients
Bove (2006)
19 ET (12, arms only; 7, +head) 19 healthy controls Parisi (2006) 16 ET w/ head tremor 14 ET w/o head tremor 28 healthy controls Kronenbuerger 25 ET (18 w/ (2009) postural/kinetic tremor; 7 w/ cerebellar signs) 25 healthy controls Hoskovcova 30 ET (2012) 25 healthy controls
Experimental design
Results
Static posturography with eyes open and closed during quiet stance and performance of mental or motor task; center of foot pressure and postural sway measured Subjects assessed using functional mobility performance and self-report measures (Timed Up & Go; Dynamic Gait Index; Berg Balance Scale; etc.) Balance control measured by tandem treadmill gait & static and dynamic posturography
Balance control is only minimally affected in ET; patients with head involvement and longer disease duration tend to present a reduced postural stability Subjects with ET showed reduced functional mobility, especially those with head tremor
Subjects underwent posturography and gait assessment; assessment via ABC, FAB, ICARS scales; tremor evaluation via rating scale and accelerometry
ET patients showed increased number of missteps, shortened stride length w/ tandem gait; both ET groups had increased postural instability in dynamic posturography – more so in ET subjects w/ cerebellar signs. Confirms ET is associated with cerebellar impairment. ET subjects exhibited: lower tandem gait velocity; more missteps; increased postural sway. Step width in normal gait of ET subjects increased w/ midline tremor subscore of TRS. Significant correlations found between age and quantitative measures of gait.
ABC = Activities-Specific Balance Confidence. FAB = Fullerton Advanced Balance. ICARS = International Cooperative Ataxia Rating Scale. TRS = tremor rating scale.
strongly affected compared to postural tremor. As intentional tremor has been attributed to a greater extent to cerebellar dysfunction, the author's findings imply the possibility of two separate mechanisms underlying the two tremor entities. Fasano et al. reported that therapeutic DBS intensity levels suppress both tremor and cerebellar dysfunction,
while supra-therapeutic stimulation (defined by increasing the amplitude and pulse width until decomposition of movement in the finger to nose test) extinguishes tremor and results in the return of cerebellar dysfunction, implying that the variation of DBS intensity may affect two different circuits: the cortico-thalamo-cortical loop for tremor reduction
Table 2 Summary of studies investigating the effects of DBS on gait and balance in ET. Author (year)
# of patients
Experimental design
DBS settings
Ondo (2006)
13 ET w/ VIM DBS
Computerized posturography
DBS-on DBS-off
Pahwa (2006)
26 ET w/ VIM DBS (18, unilateral; 8, bilateral) 13 ET w/ bilateral VIM DBS
Earhart (2009)
Fasano (2009)
11 ET w/ thalamic DBS
Kronenbuerger 12 ET w/ (2009) thalamic DBS
Hwynn (2011)
38 ET (25 w/ unilateral; 13 w/ bilateral VIM DBS)
Pedrosa (2013)
16 ET w/ bilateral thalamic DBS
Results
With DBS-on, ET subjects showed significant improvement over trials on dorsiflexion texts. No such adaptation over trials was shown with DBS-off. Falls lessened with DBS-on in ET subjects. Bilateral VIM DBS mostly improved balance, but may worsen other specific features. Evaluated using Fahn-Tolosa-Marin tremor rating scale DBS-on In ET patients receiving bilateral stimulation, 25% experienced DBS-off balance difficulties. Disequilibrium, balance difficulties, and abnormal gait were more common in bilateral ET subjects than in unilateral. Standard and tandem walking; Berg Balance Score, DBS-on Compared to controls, subjects w/ ET walked significantly Balance confidence, Timed Up-and-Go DBS-off more slowly for both standard and tandem walking, spent lower percentage of gait cycle in single limb support, higher percentage in double support, lower Berg balance scores, greater time to perform Timed Up-and-Go. No significant differences in any gait or balance measure for DBS-on vs. DBS-off. However, effects of DBS on gait and balance were highly variable between individuals. Locomotion assessed via: overground gait and tandem DBS-on During DBS-off, subjects exhibited ataxia in all assessments, gait; balance-assisted treadmill tandem gait; DBS-off which improved during DBS-on and worsened again during unassisted treadmill gait Supratherapeutic supratherapeutic stimulation. These improvements in ataxia were not a function of reduced tremor in lower limbs or torso. Balance control measured by tandem treadmill gait & DBS-on DBS of ventrolateral thalamus did not significantly affect static and dynamic posturography DBS-off balance control, as measured via performance in tandem gait or posturography; ET patients with and without clinical cerebellar impairment showed increased postural instability; confirms that ET is associated with cerebellar impairment. Retrospective chart review; FTM TRS & individual No stimulation 21% of full cohort experienced worsened gait with falls upper extremity scores. Recorded at: baseline, setting variation; post-DBS. Baseline pre-morbid gait difficulty varied: 61% in 6-months post-unilateral/6–12 months post-bilateral Evaluations pre- unilateral cases; 46% in bilateral cases. Post-op gait worsening surgery. and post-DBS associated with more severe disease; older age (weak Further categorized by baseline and post-DBS gait correlation); & pre-op balance difficulty, especially w/ difficulties: −gait pre/−gait post; −gait pre/+gait bilateral surgery. Higher baseline TRS associated with post-op post; +gait pre/++gait post; +gait pre/−+gait post gait worsening. Tremor rating scale and ultrasound-based tremor HFS HFS successfully treats tremor; LFS increases tremor amplitude measurements LFS (10 Hz) compared with DBS-off; more severe effect of LFS on DBS-off intentional tremor compared with postural tremor – implying different mechanisms responsible for both types of tremor
HFS = high frequency (deep brain) stimulation. LFS = low frequency (deep brain) stimulation. DBS-on = deep brain stimulation on. DBS-off = deep brain stimulation off. Supratherapeutic = defined by increasing amplitude and pulse width until exposure of cerebellar dysfunction is apparent.
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and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation) [9]. Impaired gait has been conventionally held as a potential adverse effect of bilateral DBS with reports ranging from 26% to 55% [7,12]. Management of imbalance can be challenging, as reduction in stimulation parameters commonly leads to tremor recurrence or no effect on disequilibrium. However, others have presented contradictory evidence showing that DBS has no adverse effect on gait and balance in unilateral and bilateral stimulation [4,11] and even a positive effect on symptoms dependent on the mode of stimulation [9,10]. Although thalamic DBS is a safe and effective treatment for medically refractory ET, increasing reports suggest that the posterior subthalamic area might be a more efficient target [13,14]. Nevertheless, both targets required HFS for therapeutic purposes with frequencies typically ranging between 160 and 180 Hz. Increased frequencies commonly translate in additional tremor improvement, although systematic analysis of specific programming parameters modifications are lacking. It is thought that thalamic DBS exerts its effects through modulation of cerebellothalamo-cortical connections by changing the pattern of neuronal activity [15]. Because of the occurrence of a possible U-shaped correlation between stimulation strength and cerebellar findings couple with potential exacerbation of cerebellar findings with supratherapeutic stimulation levels, we aimed to assess the efficacy of reduction of DBS frequency in patients complaining of worsening balance after HFS thalamic DBS. In this report, we present the effects of DBS frequency variation on tremor control and disequilibrium in a cohort of 4 ET patients presenting with worsening disequilibrium and ataxia following treatment with thalamic DBS. Additionally, we present a review of recent literature regarding the topic. 2. Methods We performed a PubMed search using different combinations between the terms ‘imbalance,’ ‘disequilibrium,’ ‘falls’, ‘unsteadiness’ and ‘Deep Brain Stimulation/DBS’. The respective medical subheading in the search strategy was included when available. Relevant case reports, case series and studies that were published in peer-reviewed journals and available in full text and written in English were included in our review (Table 2). All participants were diagnosed with essential tremor according to the criteria of the consensus statement of the Movement Disorder Society Group [16]. Albany Medical College institutional review board approved the study. Informed consent was obtained from all patients after reviewing study protocol. Patients were recruited and identified during routine outpatient clinic follow up from June 2013 to August 2014. Patients with unilateral or bilateral thalamic VIM DBS were considered. A semi-structured interview screening for balance difficulties was conducted by the treating neurologist (ARZ). Key inclusion criteria for participation in the study included 1) subjective reports of worsening balance after surgery, 2) diagnosis of ET based on Movement Disorder Society guidelines refractory to medical treatment, 3) disease duration N10 years, and 4) stable dose of medications for tremor at least one
month prior to intervention and during study duration. Key exclusion criteria included 1) the presence of secondary factors leading to imbalance including weakness, musculoskeletal problems, vestibular dysfunction, visual impairment, or severe proprioceptive deficits, 2) untreated or clinically significant depression or psychiatric disease, 3) marked cognitive impairment and 4) other significant conditions that could interfere with assessments or participation. A total of 12 patients were identified during the screening period but 8 patients were excluded because of the presence of additional causes of disequilibrium (6) and denial of participation in the study (2). Other overt causes of imbalance in these patients included the presence of peripheral neuropathy with sensory ataxia due to Diabetes Mellitus (2) or idiopathic (1), associated parkinsonism due to exposure to dopamine blocking agents leading to postural instability (1) and severe knees osteoarthritis and lumbar spine disease affecting ambulation and equilibrium (2). DBS programming settings varied among patients based on tremor response and adverse effects but all patients were consistently programmed using HFS (170–185 Hz). Four patients with longstanding ET syndrome treated with thalamic DBS for medically-refractory ET with worsening equilibrium after surgery were identified (Table 3). DBS settings remained unchanged for at least three months prior to enrolling in the study. All patients reported the occurrence of worsening balance at different time points after surgery ranging from six to nineteen months. Unsteadiness was characterized by a feeling of disequilibrium or imbalance that lead to occasional falls and common near falls. Worsening elements of cerebellar ataxia during ambulation were noted on examination. A comprehensive neurological examination was conducted to exclude DBS malfunction or other causes of worsening balance and gait as described in inclusion requirements. Two patients had dominant hand, unilateral, left thalamic DBS and two patients underwent sequential, bilateral procedures. No severe gait difficulties were apparent before surgery, although mild tandem dystaxia was noted in all patients prior to DBS. Tremor control was assessed pre-operatively and at follow up using the Fahn-Tolosa-Marin (FTM) tremor rating scale. We utilized a lateralized FTM scale in patients with unilateral surgery. Ataxia and imbalance were assessed using the International Cooperative Ataxia Rating Scale (ICARS, posture and gait disturbance sub-scores) along with an unstructured, subject-completed clinical global impression scale (CGI) at 4 weeks after DBS programming changes. CGI scale ranges from 1 to 7, 1 indicating very much improved, 7 indicating very much worse compared with baseline. 3. Procedures First, all patients had stereotactic placement of unilateral or bilateral Thalamic VIM DBS electrodes as previously described [17]. Briefly, the DBS procedure was conducted utilizing the Leksell stereotactic frame. Targeting was performed using a combination of AC-PC coordinates and adjustments based on direct imaging relative to MRI visible structures along with microelectrode recordings to define the borders of VIM and sensory thalamus. Adequate final postoperative electrode
Table 3 Patient's demographics. Patient No.
Age of ET diagnosis (years)
Sex
Age at time of VIM DBS surgery (years)
Time to report imbalance after DBS (months)
1 2 3
52 21 32
Female Male Male
9 months 14 months 19 months after right VIM
4
40
Male
Mean
36.25
Standard deviation
13.07
68 (unilateral left) 44 (unilateral left) 58 (left VIM) 59 (right VIM) 66 (left VIM) 73 (right VIM) L: 59 R: 66 L: 10.89 R: 9.90 L: 4 R: 2
N
4
6 months after right VIM
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Table 4 patient's programming settings, tremor and ICARS scores. Patient
FTM tremor scale after maximized tremor control?
1
3
2
9
3
15
4
5
Programming settings for best tremor control, amplitude/pulse width/frequency
ICARS ICARS subscores subscores after DBS frequency adjustments
Programming settings for improvement in balance, amplitude/pulse width/frequency
CGI-S scale improvement at 4 weeks
Percentage Change in ICARS subscores
Contact 1 negative, 2 positive, 2.1/90/185 Contact 3 negative, contact 2 positive, 2.6/90/185. Right VIM contact 2 negative, 1 positive, 2.0/90/170. Left VIM contact 0 positive, 1 negative, 2 negative, 4.1/60/170. Left VIM contact 2 positive, 1 negative, 2.7/60/185.
5
3
2
40%
8
5
8
6
6
4
Contact 1 negative, contact 2 positive, 2.1/90/130. Contact 3 negative, 2 positive, 2.1/90/130. Right VIM contact 2 negative, 1 positive, 2.0/90/130. Left VIM contact 0 positive, 1 negative, 2 negative, 4.1/60/130. Left VIM contact 2 positive, 1 negative, 2.7/60/130
Right VIM contact 5 positive, 4 negative, 3.1/60/185. Mean Standard deviation
8 5.29
1 2
2
37.5% 25%
33.3%
Right VIM contact 5 positive, 4 negative, 3.1/60/130 6.75 1.5
4.50 1.29
33.95%
Fahn-Tolosa-Marin (FTM) tremor rating scale. International Cooperative Ataxia Rating Scale (ICARS).
locations were confirmed utilizing volumetric CT scanning registered to the preoperative Brain MRI using BrainLab (https://www.brainlab.com/ ). Patients underwent DBS programming for maximal tremor control over the following months. Once disequilibrium was reported, changes in stimulation amplitude utilizing ventral contacts did not improve or worsened disequilibrium and caused other side effects (dysarthria or paresthesia) and activation of more dorsal electrodes compromised tremor control. Reduction in voltage in unipolar mode leads to worsening tremors. Interestingly, all patients were receiving unipolar stimulation at the time they reported imbalance. Although recent reports suggest that tremor progression and possible cerebellar features are related to disease progression [18], assessment of imbalance after turning stimulators off provided improvement in patient's gait difficulties supporting the role of neurostimulation to their disequilibrium. In patients with bilateral procedures, no difference in equilibrium was noted turning either left or right hemisphere stimulators but improvement in balance was observed when both stimulators were turned off. Patients reported improvement in balance within an hour after being off stimulation. In patients with bilateral DBS, programming sessions were aimed to maximize tremor benefit with reduction in potential side effects commonly seen with bilateral surgery, particularly dysarthria. Subjects' DBS parameters were continued at the same pulse width, voltage, and combinations of active cathodes and anodes determined to be effective. A stable clinical tremor response to thalamic DBS for at least 1 month was required before assessments. Differences in patients' individual regional anatomy, lead location, and propensity to experience side effects prompted the decision to forego standardizing DBS stimulation parameters and electrode configurations in subjects. Specific differences in programming settings among patients (primarily amplitude and pulse width (PW) in patients 3 and 4) provided the best tremor response without inducing adverse effects. A specific programming paradigm beneficial to one patient might cause partial benefit or side effects to the next one. Furthermore, controlling for the total electrical charge—determined by the product of the electrical current, pulse width, and frequency—as a way to reduce variability would have failed to ensure optimal therapeutic effect. Initially, all patients were programmed in bipolar mode using HFS between 170 and 185 Hz to minimize side effects and with adequate tremor control. Reduction in DBS frequency to the lowest setting effective for tremor control in 10– 20 Hz reduction intervals was conducted with brief washout periods as performed by other groups [19]. Tremor was assessed after every interval by monitoring changes in Archimedes' spiral and ability to drink form a cup using one hand. After monitoring for acute change in
symptoms, complete assessments including ICARS were conducted 30 min after final stimulation settings were determined. Patients were reevaluated 4 weeks later and they were instructed to monitor for changes in their symptoms. 4. Results Patients tolerated changes well without significant change in tremor control (Table 4). No acute adverse effects were noted. At 4 weeks, there was a slight worsening but no statistical difference in tremors scores after DBS frequency reduction. All patients reported subjective improvement in balance ranging from mild to marked improvement on the CGI-S. ICARS scores following DBS frequency adjustments showed significant improvement from pre-adjustment scores (p = 0.003). Reintroducing HFS caused recurrence of imbalance and worsening ICARS scores in patients one, three and four. Patient two reported clear reappearance of a sense of unsteadiness without change in ICARS. Average ICARS score improvement was 2.25 ± 0.50 points. FTM scale score for maximized tremor correlated strongly with ICARS score prior to DBS frequency adjustments (r = 0.88), although this was not statistically significant (p = 0.118) indicating that patients with worse UE tremor are more likely to have worse gait/balance difficulties. Comparing FTM scale score with ICARS score measured after adjustments showed a strong and significant correlation (r = 0.98, p = 0.024). However, the strength of this correlation might be exaggerated as an artifact of our small sample size. The average decrease in frequency of stimulation to maintain tremor control was 51.25 ± 7.5 Hz. Age and disease duration were not found to have any significant predictive value for the FTM or ICARS scales. The patient with highest FTM scale scored had the smallest improvement, but there was not a linear relationship between tremor severity at baseline and improvement in ICARS with low frequency stimulation. 5. Discussion Increasing evidence emphasizes the role of the cerebellum in ET by clinical observations such as the impairment of the blink-reflex [20], ataxia during tandem gait [21] and cognitive and affective deficits [22, 23] resembling those in the ‘cerebellar cognitive affective syndrome’. Also, in a subset of patients, impaired balance has been shown to produce increased body sway [24] and decreased functional mobility, performance and self-reported measures of stability [6]. These abnormalities are independent of tremor severity and distribution [4,
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6,24]. The impact on daily function and relationship with stimulation parameters for tremor control is not known. There is conflicting evidence regarding the effects of DBS in ET. Although the effects of different paradigms have been studied, the heterogeneous nature of ET, leads location, and variable programming strategies contribute to the documented variability of these results. Our results suggest a relationship between the effects of HFS and worsening balance in ET patients implanted with bilateral or unilateral DBS. Reduction in frequency provided improvement in balance measured using ICARS subscores. In prior studies, specific balance assessments were paired with a variety of stimulation settings, including unipolar or double unipolar stimulation, variable PWs and primarily high frequencies (mean 165 Hz). Increased stimulation charge broadens the electric field radius and changes the composition of stimulated neuronal elements leading to a narrow therapeutic threshold for gait and tremor control [25]. The ultimate electrical charge might account for changes observed in different studies where disadvantageous consequences of imbalance were noted with thalamic stimulation. Additionally, most of previous studies analyzing the effects of DBS on balance utilized an OFF and ON paradigm, not permitting to assess specific differences in stimulation contacts or programming variables. In our cohort, there was not exacerbation of tremor after frequency reduction and we did not modify other stimulation settings purposefully. It is unclear why patients complained of imbalance months or years after initial implantation but we suspect that DBS causes impaired equilibrium only after a specific and individual threshold for cerebellar dysfunction has been crossed because of disease progression. Additionally, it is possible that DBS disrupted the function and role of thalamic VIM in modulation of cerebellar or vestibular system in our patients [26]. Further research is needed to clarify this point. Additionally, all our patients received solely bipolar stimulation. Although bilateral surgery has been associated with worsening balance, other groups have reported gait and disequilibrium with unilateral cases [12]. Importantly, stimulation parameters leading to imbalance and their relationship to anatomical site of stimulation need further assessment. Fasano et al. reported that stereotactic evaluation of stimulating electrodes revealed localization of the most efficacious contacts outside the thalamus within the prelemniscal radiation [9] as previously reported by other centers [27]. The simple protocol utilized in our study limits the number of confounding DBS variables and the restriction to assess only during on/off stimulation. We acknowledge the limitations in our analysis including the small sample size and the lack of more objective measures for balance assessment including tandem treadmill gait & static and dynamic posturography. Because of these limitations, we cannot determine a specific effect of DBS laterality or effects of specific locations within the thalamus. However, the design aimed to minimize other confounding variables during DBS programming. Additional studies using dynamic testing and larger-scale prospective studies are required to validate our findings and further discern the relationship between stimulation contact location and the effects of different programming settings in cerebellar findings in ET. A control group would also be needed in order to compare progression of gait difficulties in ET cohorts not undergoing DBS implantation. Additionally, future studies would need to address baseline preoperative gait and balance dysfunction comparisons to OFF-stimulation and ON-stimulation postoperative assessments (with attention to washout effects). 6. Conclusions The recognition of balance difficulties and cerebellar features in patients with ET has expanded the spectrum of clinical features observed in the disease. The effects of unilateral or bilateral thalamic DBS on equilibrium are complex with conflicting results and variable observations seen in multiple testing settings. The heterogeneity of testing conditions makes it difficult to draw definitive conclusions or to compare different results. Because of the clinical implications associated with worsening
balance in ET patients, improved treatments to maximize tremor control and mitigate side effects after DBS are needed. Identifying patients at risk for disequilibrium along with improving our understanding of the relationship between imbalance, lead locations and stimulation parameters is critical. Our study suggests a direct relation between stimulation frequency and imbalance after DBS. Despite our study limitations, our findings provide proof of concept to consider judicious reduction of stimulation frequency after maximizing tremor control to improve disequilibrium after bilateral or unilateral thalamic DBS in ET. Larger prospective, randomized, controlled studies are warranted. Conflict of interest None. Disclosures Dr. Julie Pilitsis is a consultant for Medtronic, St. Jude and Boston Scientific and receives grant support from Jazz Pharmaceuticals, Medtronic, Boston Scientific, St. Jude and NIH 1R01CA166379. She is medical advisor for Centauri and has stock equity. There was no support for this paper from any company/institution. Dr. Ramirez-Zamora has received consultant honoraria from Teva pharmaceuticals. The Phyllis E. Dake Endowed Chair in Movement Disorders supported this study. The institution and not Dr. Ramirez-Zamora receives grant support from Medtronic and Boston Scientific. Dr. Ramirez-Zamora has participated as a site PI and/or co-I for several NIH and industry sponsored trials over the years but has not received honoraria. Boggs, Hans has no conflict of interest or financial disclosures. References [1] E.D. Louis, J.J. Ferreira, How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor, Mov. Disord. 25 (5) (2010) 534–541. [2] V. Chandran, P.K. Pal, Essential tremor: beyond the motor features, Parkinsonism Relat. Disord. 18 (5) (2012) 407–413. [3] D. Arkadir, E.D. Louis, The balance and gait disorder of essential tremor: what does this mean for patients? Ther. Adv. Neurol. Disord. 6 (4) (2013) 229–236. [4] M. Kronenbuerger, J. Konczak, W. Ziegler, P. Buderath, B. Frank, V.A. Coenen, et al., Balance and motor speech impairment in essential tremor, Cerebellum 8 (3) (2009) 389–398. [5] M. Hoskovcova, O. Ulmanova, O. Sprdlik, T. Sieger, J. Novakova, R. Jech, et al., Disorders of balance and gait in essential tremor are associated with midline tremor and age, Cerebellum 12 (1) (2013) 27–34. [6] S.L. Parisi, M.E. Heroux, E.G. Culham, K.E. Norman, Functional mobility and postural control in essential tremor, Arch. Phys. Med. Rehabil. 87 (10) (2006) 1357–1364. [7] R. Pahwa, K.E. Lyons, S.B. Wilkinson, R.K. Simpson Jr., W.G. Ondo, D. Tarsy, et al., Long-term evaluation of deep brain stimulation of the thalamus, J. Neurosurg. 104 (4) (2006) 506–512. [8] D.J. Pedrosa, M. Auth, C. Eggers, L. Timmermann, Effects of low-frequency thalamic deep brain stimulation in essential tremor patients, Exp. Neurol. 248 (2013) 205–212. [9] A. Fasano, J. Herzog, J. Raethjen, F.E. Rose, M. Muthuraman, J. Volkmann, et al., Gait ataxia in essential tremor is differentially modulated by thalamic stimulation, Brain 133 (Pt 12) (2010) 3635–3648. [10] W.G. Ondo, M. Almaguer, H. Cohen, Computerized posturography balance assessment of patients with bilateral ventralis intermedius nuclei deep brain stimulation, Mov. Disord. 21 (12) (2006) 2243–2247. [11] G.M. Earhart, B.R. Clark, S.D. Tabbal, J.S. Perlmutter, Gait and balance in essential tremor: variable effects of bilateral thalamic stimulation, Mov. Disord. 24 (3) (2009) 386–391. [12] N. Hwynn, C.J. Hass, P. Zeilman, J. Romrell, Y. Dai, S.S. Wu, et al., Steady or not following thalamic deep brain stimulation for essential tremor, J. Neurol. 258 (9) (2011) 1643–1648. [13] M.T. Barbe, L. Liebhart, M. Runge, J. Deyng, E. Florin, L. Wojtecki, et al., Deep brain stimulation of the ventral intermediate nucleus in patients with essential tremor: stimulation below intercommissural line is more efficient but equally effective as stimulation above, Exp. Neurol. 230 (1) (2011) 131–137. [14] P. Blomstedt, U. Sandvik, A. Fytagoridis, S. Tisch, The posterior subthalamic area in the treatment of movement disorders: past, present, and future, Neurosurgery 64 (6) (2009) 1029–1038 (discussion 38-42). [15] T.R. Anderson, B. Hu, K. Iremonger, Z.H. Kiss, Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation-induced tremor arrest, J. Neurosci. 26 (3) (2006) 841–850.
A. Ramirez-Zamora et al. / Journal of the Neurological Sciences 367 (2016) 122–127 [16] G. Deuschl, P. Bain, M. Brin, Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee, Mov Disord. 13 (Suppl. 3) (1998) 2–23. [17] J.G. Pilitsis, L.V. Metman, J.R. Toleikis, L.E. Hughes, S.B. Sani, R.A. Bakay, Factors involved in long-term efficacy of deep brain stimulation of the thalamus for essential tremor, J. Neurosurg. 109 (4) (2008) 640–646. [18] C.G. Favilla, D. Ullman, A. Wagle Shukla, K.D. Foote, C.E. Jacobson, M.S. Okun, Worsening essential tremor following deep brain stimulation: disease progression versus tolerance, Brain 135 (Pt 5) (2012) 1455–1462. [19] E. Moro, R.J. Esselink, J. Xie, M. Hommel, A.L. Benabid, P. Pollak, The impact on Parkinson's disease of electrical parameter settings in STN stimulation, Neurology 59 (5) (2002) 706–713. [20] M. Kronenbuerger, M. Gerwig, B. Brol, F. Block, D. Timmann, Eyeblink conditioning is impaired in subjects with essential tremor, Brain 130 (Pt 6) (2007) 1538–1551. [21] H. Stolze, G. Petersen, J. Raethjen, R. Wenzelburger, G. Deuschl, The gait disorder of advanced essential tremor, Brain 124 (Pt 11) (2001) 2278–2286. [22] F. Bermejo-Pareja, Essential tremor–a neurodegenerative disorder associated with cognitive defects? Nat. Rev. Neurol. 7 (5) (2011) 273–282.
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[23] A.I. Troster, S.P. Woods, J.A. Fields, K.E. Lyons, R. Pahwa, C.I. Higginson, et al., Neuropsychological deficits in essential tremor: an expression of cerebello-thalamo-cortical pathophysiology? Eur. J. Neurol. 9 (2) (2002) 143–151. [24] M. Bove, L. Marinelli, L. Avanzino, R. Marchese, G. Abbruzzese, Posturographic analysis of balance control in patients with essential tremor, Mov. Disord. 21 (2) (2006) 192–198. [25] Z.H. Kiss, D.M. Mooney, L. Renaud, B. Hu, Neuronal response to local electrical stimulation in rat thalamus: physiological implications for mechanisms of deep brain stimulation, Neuroscience 113 (1) (2002) 137–143. [26] B. Baier, T. Vogt, F. Rohde, H. Cuvenhaus, J. Conrad, M. Dieterich, Deep brain stimulation of the nucleus ventralis intermedius: a thalamic site of graviceptive modulation, Brain Struct. Funct. (2015). [27] J. Herzog, W. Hamel, R. Wenzelburger, M. Potter, M.O. Pinsker, J. Bartussek, et al., Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor, Brain 130 (Pt 6) (2007) 1608–1625.