Thalamic short pulse stimulation diminishes adverse effects in essential tremor patients

ObjectiveTo investigate the effect of directional current steering and short pulse stimulation in the ventral intermediate thalamic nucleus (VIM) on stimulation-induced side effects in patients with essential tremor.MethodsWe recruited 8 patients with essential tremor in a stable postoperative condition (>3 months after electrode implantation of deep brain stimulation [DBS] electrodes) with segmented contacts implanted in the VIM. Tremor severity on acute stimulation was assessed by the Fahn-Tolosa-Marin Tremor Rating Scale. Cerebellar impairment was evaluated with the International Cooperative Ataxia Rating Scale. Patients rated paresthesia intensity with a visual analog scale.ResultsIn all patients, tremor was reduced to the same extent by VIM stimulation regardless of pulse width using energy dose–equivalent amplitudes. Short pulse stimulation diminished stimulation-induced ataxia of the upper extremities and paresthesia compared with conventional parameters. Directional steering with monopolar stimulation of single segments successfully suppressed tremor but also induced ataxia. No differences in adverse effects were found between single-segment stimulation conditions.ConclusionThese proof-of-principle findings provide evidence that acute short pulse stimulation is superior to directional steering in the subthalamic area to decrease stimulation-induced side effects while preserving tremor suppression effects in patients with tremor.Classification of evidenceThis study provides Class IV evidence that for patients with tremor with thalamic DBS, acute short pulse stimulation reduces adverse effects, while directional steering does not provide a generalizable benefit regarding adverse effects.

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MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes

Neurology ◽

10.1212/wnl.0000000000004268 ◽

2017 ◽

Vol 89 (8) ◽

pp. 771-775 ◽

Cited By ~ 34

Author(s):

Alfonso Fasano ◽

Maheleth Llinas ◽

Renato P. Munhoz ◽

Eugen Hlasny ◽

Walter Kucharczyk ◽

...

Keyword(s):

Side Effects ◽

Essential Tremor ◽

Focused Ultrasound ◽

Rating Scale ◽

Invasive Technique ◽

Sustained Improvement ◽

Future Studies ◽

Mri Guided

Objective:To report the 6-month single-blinded results of unilateral thalamotomy with MRI-guided focused ultrasound (MRgFUS) in patients with tremors other than essential tremor.Methods:Three patients with tremor due to Parkinson disease, 2 with dystonic tremor in the context of cervicobrachial dystonia and writer's cramp, and 1 with dystonia gene–associated tremor underwent MRgFUS targeting the ventro-intermedius nucleus (Vim) of the dominant hemisphere. The primary endpoint was the reduction of lateralized items of the Tremor Rating Scale of contralateral hemibody assessed by a blinded rater.Results:All patients achieved a statistically significant, immediate, and sustained improvement of the contralateral tremor score by 42.2%, 52.0%, 55.9%, and 52.9% at 1 week and 1, 3, and 6 months after the procedure, respectively. All patients experienced transient side effects and 2 patients experienced persistent side effects at the time of last evaluation: hemitongue numbness and hemiparesis with hemihypoesthesia.Conclusions:Vim MRgFUS is a promising, incision-free, but nevertheless invasive technique to effectively treat tremors other than essential tremor. Future studies on larger samples and longer follow-up will further define its effectiveness and safety.Clinicaltrials.gov identifier:NCT02252380.Classification of evidence:This study provides Class IV evidence that for patients with tremor not caused by essential tremor, MRgFUS of the Vim improves the tremor of the contralateral hemibody at 6 months.

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DBS of the PSA and the VIM in essential tremor

Neurology ◽

10.1212/wnl.0000000000005956 ◽

2018 ◽

Vol 91 (6) ◽

pp. e543-e550 ◽

Cited By ~ 43

Author(s):

Michael T. Barbe ◽

Paul Reker ◽

Stefanie Hamacher ◽

Jeremy Franklin ◽

Daria Kraus ◽

...

Keyword(s):

Side Effects ◽

Essential Tremor ◽

Clinical Benefit ◽

Double Blind ◽

Crossover Phase ◽

Ventral Intermediate Nucleus ◽

Frequency Of Stimulation

ObjectiveTo evaluate deep brain stimulation (DBS) of the posterior subthalamic area (PSA) in essential tremor (ET) and compare it to the ventral intermediate nucleus of the thalamus (VIM) in terms of stimulation efficacy, efficiency, and side effects.MethodsDBS leads were implanted such that contacts were placed in the VIM, on the intercommissural line, and in the PSA. Thirteen patients with ET entered a randomized, double-blind crossover phase and completed a 1-year follow-up.ResultsPSA-DBS significantly reduced tremor severity and improved quality of life. There were no relevant differences in quality and frequency of stimulation side effects between VIM and PSA, with a tendency toward greater tremor improvement with PSA stimulation. Clinical benefit was achieved at significantly lower stimulation amplitudes in the PSA. The majority of patients remained with PSA-DBS after 1 year.ConclusionIn accordance with previous retrospective investigations, our prospective data suggest that PSA-DBS is at least equally effective as but possibly more efficient than VIM-DBS.Classification of evidenceThis study provides Class I evidence that for patients with essential tremor, PSA-DBS is not significantly different from VIM-DBS in suppressing tremor, but clinical benefit from PSA-DBS is attained at lower stimulation amplitudes.

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Multimodal MRI for MRgFUS in essential tremor: post-treatment radiological markers of clinical outcome

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-322745 ◽

2020 ◽

Vol 91 (9) ◽

pp. 921-927

Author(s):

Anish N Kapadia ◽

Gavin J B Elias ◽

Alexandre Boutet ◽

Jürgen Germann ◽

Aditiya Pancholi ◽

...

Keyword(s):

Adverse Effects ◽

Clinical Outcome ◽

Essential Tremor ◽

Focused Ultrasound ◽

Lesion Size ◽

Post Treatment ◽

Medial Lemniscus ◽

Invasive Treatment ◽

Tremor Suppression ◽

Registration Number

BackgroundMRI-guided focused ultrasound (MRgFUS) thalamotomy is a promising non-invasive treatment option for medication-resistant essential tremor. However, it has been associated with variable efficacy and a relatively high incidence of adverse effects.ObjectivesTo assess the evolution of radiological findings after MRgFUS thalamotomy and to evaluate their significance for clinical outcomes.MethodsNinety-four patients who underwent MRgFUS between 2012 and 2017 were retrospectively evaluated. Lesion characteristics were assessed on routine MRI sequences, as well as with tractography. Relationships between imaging appearance, extent of white matter tract lesioning (59/94, on a 4-point scale) and clinical outcome were investigated. Recurrence was defined as >33% loss of tremor suppression at 3 months relative to day 7.ResultsAcute lesions demonstrated blood products, surrounding oedema and peripheral diffusion restriction. The extent of dentatorubrothalamic tract (DRTT) lesioning was significantly associated with clinical improvement at 1 year (t=4.32, p=0.001). Lesion size decreased over time (180.8±91.5 mm3 at day 1 vs 19.5±19.3 mm3 at 1-year post-treatment). Higher post-treatment oedema (t=3.59, p<0.001) was associated with larger lesions at 3 months. Patients with larger lesions at day 1 demonstrated reduced rates of tremor recurrence (t=2.67, p=0.019); however, lesions over 170 mm3 trended towards greater incidence of adverse effects (sensitivity=0.60, specificity=0.63). Lesion encroachment on the medial lemniscus (Sn=1.00, Sp=0.32) and pyramidal tract (Sn=1.00, Sp=0.12) were also associated with increased adverse effects incidence.ConclusionLesion size at day 1 predicts symptom recurrence, with fewer recurrences seen with larger lesions. Greater DRTT lesioning is associated with treatment efficacy. These findings may have implications for lesion targeting and extent.Trial registration numberNCT02252380.

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Longitudinal follow-up with VIM thalamic deep brain stimulation for dystonic or essential tremor

Neurology ◽

10.1212/wnl.0000000000008875 ◽

2020 ◽

Vol 94 (10) ◽

pp. e1073-e1084 ◽

Cited By ~ 6

Author(s):

Takashi Tsuboi ◽

Zakia Jabarkheel ◽

Pamela R. Zeilman ◽

Matthew J. Barabas ◽

Kelly D. Foote ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Essential Tremor ◽

Brain Stimulation ◽

Rating Scale ◽

Statistical Significance ◽

Ventral Intermediate Nucleus ◽

Deep Brain

ObjectiveTo assess longitudinal tremor outcomes with ventral intermediate nucleus deep brain stimulation (VIM DBS) in patients with dystonic tremor (DT) and to compare with DBS outcomes in essential tremor (ET).MethodsWe retrospectively investigated VIM DBS outcomes for 163 patients followed at our center diagnosed with either DT or ET. The Fahn-Tolosa-Marin tremor rating scale (TRS) was used to assess change in tremor and activities of daily living (ADL) at 6 months, 1 year, 2–3 years, 4–5 years, and ≥6 years after surgery.ResultsTwenty-six patients with DT and 97 patients with ET were analyzed. Compared to preoperative baseline, there were significant improvements in TRS motor up to 4–5 years (52.2%; p = 0.032) but this did not reach statistical significance at ≥6 years (46.0%, p = 0.063) in DT, which was comparable to the outcomes in ET. While the improvements in the upper extremity tremor, head tremor, and axial tremor were also comparable between DT and ET throughout the follow-up, the ADL improvements in DT were lost at 2–3 years follow-up.ConclusionOverall, tremor control with VIM DBS in DT and ET was comparable and remained sustained at long term likely related to intervention at the final common node in the pathologic tremor network. However, the long-term ADL improvements in DT were not sustained, possibly due to inadequate control of concomitant dystonia symptoms. These findings from a large cohort of DT indicate that VIM targeting is reasonable if the tremor is considerably more disabling than the dystonic features.Classification of evidenceThis study provides Class IV evidence that VIM DBS improves tremor in patients with DT or ET.

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Computerised analysis of writing and drawing by essential tremor phenotype

BMJ Neurology Open ◽

10.1136/bmjno-2021-000212 ◽

2021 ◽

Vol 3 (2) ◽

pp. e000212

Author(s):

James Peters ◽

Mohammod Abdul Motin ◽

Laura Perju-Dumbrava ◽

Sheik Mohammed Ali ◽

Catherine Ding ◽

...

Keyword(s):

Essential Tremor ◽

Consensus Statement ◽

Rating Scale ◽

Limb Movement ◽

The Mean ◽

Drawing Tasks ◽

Computerised Analysis ◽

Healthy Participants ◽

Biological Differences

We investigated whether computerised analysis of writing and drawing could discriminate essential tremor (ET) phenotypes according to the 2018 Consensus Statement on the Classification of Tremors. The Consensus scheme emphasises soft additional findings, mainly motor, that do not suffice to diagnose another tremor syndrome. Ten men and nine women were classified by blinded assessors according to Consensus Axis 1 definitions of ET and ET plus. Blinded scoring of tremor severity and alternating limb movement was also conducted. Twenty healthy participants acted as controls. Four writing and three drawing tasks were performed on a Wacom Intuos Pro Large digital tablet with a pressure-sensor mounted ink pen. Sixty-seven computerised measurements were obtained, comprising static (dimensional and temporal), kinematic and pen pressure features. The mean age of ET participants was 67.2±13.0 years and mean tremor duration was 21.7±19.0 years. Six were classified as ET, five had one plus feature and eight had two plus features. The computerised analysis could predict the presence and number of ET plus features. Measures of acceleration and variation of pen pressure performed strongly to separate ET phenotypes (p<0.05). Plus features were associated with higher scores on the Fahn-Tolosa-Marin Tremor Rating Scale (p=0.001) and it appeared that ET groups were mainly being separated according to severity of tremor and by compensatory manoeuvres used by participants with more severe tremor. There were, in addition, a small number of negative kinematic correlations suggesting some slowness with ET plus. Abnormal repetitive limb movement was also correlated with tremor severity (R=0.57) by clinical grading. Critics of the Consensus Statement have drawn attention to weaknesses of the ET plus concept in relation to duration and severity of ET. This classification of ET may be too biased towards tremor severity to assist in distinguishing underlying biological differences by clinical measurement.

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Stimulation-Induced Side Effects of Deep Brain Stimulation in the Ventralis Intermedius and Posterior Subthalamic Area for Essential Tremor

Frontiers in Neurology ◽

10.3389/fneur.2021.678592 ◽

2021 ◽

Vol 12 ◽

Author(s):

Myung Ji Kim ◽

Kyung Won Chang ◽

So Hee Park ◽

Won Seok Chang ◽

Hyun Ho Jung ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Side Effects ◽

Essential Tremor ◽

Brain Stimulation ◽

Rating Scale ◽

Gait Disturbance ◽

Electrode Implantation ◽

Electrode Contact ◽

Deep Brain ◽

Stimulation Of

Deep brain stimulation (DBS) targeting the ventralis intermedius (VIM) nucleus of the thalamus and the posterior subthalamic area (PSA) has been shown to be an effective treatment for essential tremor (ET). The aim of this study was to compare the stimulation-induced side effects of DBS targeting the VIM and PSA using a single electrode. Patients with medication-refractory ET who underwent DBS electrode implantation between July 2011 and October 2020 using a surgical technique that simultaneously targets the VIM and PSA with a single electrode were enrolled in this study. A total of 93 patients with ET who had 115 implanted DBS electrodes (71 unilateral and 22 bilateral) were enrolled. The Clinical Rating Scale for Tremor (CRST) subscores improved from 20.0 preoperatively to 4.3 (78.5% reduction) at 6 months, 6.3 (68.5% reduction) at 1 year, and 6.5 (67.5% reduction) at 2 years postoperation. The best clinical effect was achieved in the PSA at significantly lower stimulation amplitudes. Gait disturbance and clumsiness in the leg was found in 13 patients (14.0%) upon stimulation of the PSA and in significantly few patients upon stimulation of the VIM (p = 0.0002). Fourteen patients (15.1%) experienced dysarthria when the VIM was stimulated; this number was significantly more than that with PSA stimulation (p = 0.0233). Transient paresthesia occurred in 13 patients (14.0%) after PSA stimulation and in six patients (6.5%) after VIM stimulation. Gait disturbance and dysarthria were significantly more prevalent in patients undergoing bilateral DBS than in those undergoing unilateral DBS (p = 0.00112 and p = 0.0011, respectively). Paresthesia resolved either after reducing the amplitude or switching to bipolar stimulation. However, to control gait disturbance and dysarthria, some loss of optimal tremor control was necessary at that particular electrode contact. In the present study, the most common stimulation-induced side effect associated with VIM DBS was dysarthria, while that associated with PSA DBS was gait disturbance. Significantly, more side effects were associated with bilateral DBS than with unilateral DBS. Therefore, changing active DBS contacts to simultaneous targeting of the VIM and PSA may be especially helpful for ameliorating stimulation-induced side effects.

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Shorter pulse width reduces gait disturbances following deep brain stimulation for essential tremor

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319427 ◽

2019 ◽

Vol 90 (9) ◽

pp. 1046-1050 ◽

Cited By ~ 7

Author(s):

Daniel Kroneberg ◽

Siobhan Ewert ◽

Anne-Christiane Meyer ◽

Andrea A Kühn

Keyword(s):

Deep Brain Stimulation ◽

Side Effects ◽

Essential Tremor ◽

Brain Stimulation ◽

Pulse Width ◽

Stride Length ◽

Gait Parameters ◽

Tremor Suppression ◽

Gait Disturbances ◽

Deep Brain

ObjectiveGait disturbances are frequent side effects occurring during chronic thalamic deep brain stimulation (DBS) in patients with essential tremor (ET). Adapting stimulation settings to shorter pulse widths has been shown to reduce side effects of subthalamic DBS. Here, we assess how a reduction of pulse width changes gait performance of affected patients.MethodsSensor-based gait assessment was performed to record spatiotemporal gait parameters in 10 healthy subjects (HS) and 7 patients with ET with gait disturbances following thalamic DBS. Patients were tested during standard DBS, after 72 hours of stimulation withdrawal and at least 30 days after adjusting DBS settings to a shorter pulse width of 40 µs (DBS40PW).ResultsPatients with ET on standard DBS showed significantly higher variability of several spatiotemporal gait parameters compared with HS. Variability of stride length and range of motion of the shanks significantly decreased OFF DBS as compared with standard DBS. This improvement was maintained over 30 days with DBS40PW while providing effective tremor suppression in six out of seven patients.ConclusionShorter pulse widths may reduce gait disturbances in patients with ET that are induced by DBS while preserving a level of tremor suppression equal to standard stimulation settings.

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Lithium in the treatment of bipolar disorder - monitoring of the adverse effects

Medicinski pregled ◽

10.2298/mpns2002049o ◽

2020 ◽

Vol 73 (1-2) ◽

pp. 49-53

Author(s):

Milana Okanovic ◽

Olga Zivanovic ◽

Mina Cvjetkovic-Bosnjak ◽

Vladimir Knezevic ◽

Djendji Siladji ◽

...

Keyword(s):

Bipolar Disorder ◽

Side Effects ◽

Adverse Effects ◽

Lithium Treatment ◽

Lithium Therapy ◽

Parathyroid Function ◽

First Choice ◽

Clinically Significant ◽

American Academy Of Neurology

Introduction. Lithium therapy remains the gold standard in the treatment of bipolar disorder and clinical guidelines recommend it as the first choice for maintenance treatment of bipolar disorder. However, the use of lithium has decreased over the years, mainly due to the fear of its adverse effects. The aim of this paper was to review current literature data for the monitoring and overcoming side effects of lithium therapy in order to provide contemporary evidence for adequate lithium use. Material and Methods. A literature review of lithium therapy in bipolar disorder, using both Medline and manual searches, was performed. Classification of studies, in relation to their quality, was performed using the guidelines established by the American Academy of Neurology. Results. Despite methodological limitations of recent studies, there is irrefutable evidence that lithium therapy can cause toxicity and side effects related to renal, thyroid and parathyroid function, as well as weight gain. Conclusion. There is clear evidence that lithium can cause various side effects, but clinically significant conditions in this regard are rare and successfully treated. Literature data confirm strong efficacy of lithium and suggest its wider use in bipolar disorder. By following clinical recommendations and careful monitoring during lithium treatment, the risk of serious side effects is low compared to its efficacy.

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Optimal Parameters of Deep Brain Stimulation in Essential Tremor: A Meta-Analysis and Novel Programming Strategy

Journal of Clinical Medicine ◽

10.3390/jcm9061855 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1855

Author(s):

I. Daria Bogdan ◽

Teus van Laar ◽

D.L. Marinus Oterdoom ◽

Gea Drost ◽

J. Marc C. van Dijk ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Side Effects ◽

Essential Tremor ◽

Brain Stimulation ◽

Meta Analysis ◽

Stimulation Parameters ◽

Novel Approach ◽

Patient Reported ◽

Tremor Suppression ◽

Deep Brain

The programming of deep brain stimulation (DBS) parameters for tremor is laborious and empirical. Despite extensive efforts, the end-result is often suboptimal. One reason for this is the poorly understood relationship between the stimulation parameters’ voltage, pulse width, and frequency. In this study, we aim to improve DBS programming for essential tremor (ET) by exploring a new strategy. At first, the role of the individual DBS parameters in tremor control was characterized using a meta-analysis documenting all the available parameters and tremor outcomes. In our novel programming strategy, we applied 10 random combinations of stimulation parameters in eight ET-DBS patients with suboptimal tremor control. Tremor severity was assessed using accelerometers and immediate and sustained patient-reported outcomes (PRO’s), including the occurrence of side-effects. The meta-analysis showed no substantial relationship between individual DBS parameters and tremor suppression. Nevertheless, with our novel programming strategy, a significantly improved (accelerometer p = 0.02, PRO p = 0.02) and sustained (p = 0.01) tremor suppression compared to baseline was achieved. Less side-effects were encountered compared to baseline. Our pilot data show that with this novel approach, tremor control can be improved in ET patients with suboptimal tremor control on DBS. In addition, this approach proved to have a beneficial effect on stimulation-related complications.

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Accumulated thermal dose in MRI-guided focused ultrasound for essential tremor: repeated sonications with low focal temperatures

Journal of Neurosurgery ◽

10.3171/2019.2.jns182995 ◽

2020 ◽

Vol 132 (6) ◽

pp. 1802-1809 ◽

Cited By ~ 8

Author(s):

Ryan M. Jones ◽

Shona Kamps ◽

Yuexi Huang ◽

Nadia Scantlebury ◽

Nir Lipsman ◽

...

Keyword(s):

Essential Tremor ◽

Focused Ultrasound ◽

Rating Scale ◽

Lesion Size ◽

Thermal Dose ◽

Mr Thermometry ◽

Dose Accumulation ◽

Regression Slope ◽

Tremor Suppression ◽

Mri Guided

OBJECTIVEThe object of this study was to correlate lesion size with accumulated thermal dose (ATD) in transcranial MRI-guided focused ultrasound (MRgFUS) treatments of essential tremor with focal temperatures limited to 50°C–54°C.METHODSSeventy-five patients with medically refractory essential tremor underwent MRgFUS thalamotomy at the authors’ institution. Intraoperative MR thermometry was performed to measure the induced temperature and thermal dose distributions (proton resonance frequency shift coefficient = −0.00909 ppm/°C). In 19 patients, it was not possible to raise the focal temperature above 54°C because of unfavorable skull characteristics and/or the pain associated with cranial heating. In this patient subset, sonications with focal temperatures between 50°C and 54°C were repeated (5.1 ± 1.5, mean ± standard deviation) to accumulate a sufficient thermal dose for lesion formation. The ATD profile sizes (17, 40, 100, 200, and 240 cumulative equivalent minutes at 43°C [CEM43]) calculated by combining axial MR thermometry data from individual sonications were correlated with the corresponding lesion sizes measured on axial T1-weighted (T1w) and T2-weighted (T2w) MR images acquired 1 day posttreatment. Manual corrections were applied to the MR thermometry data prior to thermal dose accumulation to compensate for off-resonance–induced spatial-shifting artifacts.RESULTSMean lesion sizes measured on T2w MRI (5.0 ± 1.4 mm) were, on average, 28% larger than those measured on T1w MRI (3.9 ± 1.4 mm). The ATD thresholds found to provide the best correlation with lesion sizes measured on T2w and T1w MRI were 100 CEM43 (regression slope = 0.97, R2 = 0.66) and 200 CEM43 (regression slope = 0.98, R2 = 0.89), respectively, consistent with data from a previous study of MRgFUS thalamotomy via repeated sonications at higher focal temperatures (≥ 55°C). Two-way linear mixed-effects analysis revealed that dominant tremor subscores on the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (CRST) were statistically different from baseline at 3 months and 1 year posttreatment in both low-temperature (50°C–54°C) and high-temperature (≥ 55°C) patient cohorts. No significant fixed effect on the dominant tremor scores was found for the temperature cohort factor.CONCLUSIONSIn transcranial MRgFUS thalamotomy for essential tremor, repeated sonications with focal temperatures between 50°C and 54°C can accumulate a sufficient thermal dose to generate lesions for clinically relevant tremor suppression up to 1 year posttreatment, and the ATD can be used to predict the size of the resulting ablation zones measured on MRI. These data will serve to guide future clinical MRgFUS brain procedures, particularly those in which focal temperatures are limited to below 55°C.

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