Diane Huss

A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor

BACKGROUND Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor. METHODS We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort). RESULTS Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively. CONCLUSIONS MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

UPDRS activity of daily living score as a marker of Parkinson's disease progression

The activities of daily living (ADL) subscore of the Unified Parkinsons Disease Rating Scale (UPDRS) captures the impact of Parkinsons disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross‐sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections.

Imaging Findings in MR Imaging-Guided Focused Ultrasound Treatment for Patients with Essential Tremor

This study reports the imaging findings after focused ultrasound ablation of the intermedius nuclei in patients with essential tremor. Fifteen patients received follow-up MRI studies on 4 occasions after treatment. Maximal lesion size and perilesional edema predicted a good outcome and all lesions showed consistent and typical findings in the days, weeks, and months after treatment. BACKGROUND AND PURPOSE: MR imaging–guided focused sonography surgery is a new stereotactic technique that uses high-intensity focused sonography to heat and ablate tissue. The goal of this study was to describe MR imaging findings pre- and post-ventralis intermedius nucleus lesioning by MR imaging–guided focused sonography as a treatment for essential tremor and to determine whether there was an association between these imaging features and the clinical response to MR imaging–guided focused sonography. MATERIALS AND METHODS: Fifteen patients with medication-refractory essential tremor prospectively gave consent; were enrolled in a single-site, FDA-approved pilot clinical trial; and were treated with transcranial MR imaging–guided focused sonography. MR imaging studies were obtained on a 3T scanner before the procedure and 24 hours, 1 week, 1 month, and 3 months following the procedure. RESULTS: On T2-weighted imaging, 3 time-dependent concentric zones were seen at the site of the focal spot. The inner 2 zones showed reduced ADC values at 24 hours in all patients except one. Diffusion had pseudonormalized by 1 month in all patients, when the cavity collapsed. Very mild postcontrast enhancement was seen at 24 hours and again at 1 month after MR imaging–guided focused sonography. The total lesion size and clinical response evolved inversely compared with each other (coefficient of correlation = 0.29, P value = .02). CONCLUSIONS: MR imaging–guided focused sonography can accurately ablate a precisely delineated target, with typical imaging findings seen in the days, weeks, and months following the treatment. Tremor control was optimal early when the lesion size and perilesional edema were maximal and was less later when the perilesional edema had resolved.

Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy.

Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication‐refractory essential tremor. Recently, the development of transcranial, high‐intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire.

Thalamic Connectivity in Patients with Essential Tremor Treated with MR Imaging–guided Focused Ultrasound: In Vivo Fiber Tracking by Using Diffusion-Tensor MR Imaging

PURPOSE To use diffusion-tensor (DT) magnetic resonance (MR) imaging in patients with essential tremor who were treated with transcranial MR imaging-guided focused ultrasound lesion inducement to identify the structural connectivity of the ventralis intermedius nucleus of the thalamus and determine how DT imaging changes correlated with tremor changes after lesion inducement. MATERIALS AND METHODS With institutional review board approval, and with prospective informed consent, 15 patients with medication-refractory essential tremor were enrolled in a HIPAA-compliant pilot study and were treated with transcranial MR imaging-guided focused ultrasound surgery targeting the ventralis intermedius nucleus of the thalamus contralateral to their dominant hand. Fourteen patients were ultimately included. DT MR imaging studies at 3.0 T were performed preoperatively and 24 hours, 1 week, 1 month, and 3 months after the procedure. Fractional anisotropy (FA) maps were calculated from the DT imaging data sets for all time points in all patients. Voxels where FA consistently decreased over time were identified, and FA change in these voxels was correlated with clinical changes in tremor over the same period by using Pearson correlation. RESULTS Ipsilateral brain structures that showed prespecified negative correlation values of FA over time of -0.5 or less included the pre- and postcentral subcortical white matter in the hand knob area; the region of the corticospinal tract in the centrum semiovale, in the posterior limb of the internal capsule, and in the cerebral peduncle; the thalamus; the region of the red nucleus; the location of the central tegmental tract; and the region of the inferior olive. The contralateral middle cerebellar peduncle and bilateral portions of the superior vermis also showed persistent decrease in FA over time. There was strong correlation between decrease in FA and clinical improvement in hand tremor 3 months after lesion inducement (P < .001). CONCLUSION DT MR imaging after MR imaging-guided focused ultrasound thalamotomy depicts changes in specific brain structures. The magnitude of the DT imaging changes after thalamic lesion inducement correlates with the degree of clinical improvement in essential tremor.

Dexmedetomidine and arousal affect subthalamic neurons

Stereotactic neurosurgeons hesitate to employ sedation in cases requiring microelectrode recording (MER). We report our experience with dexmedetomidine during MER of subthalamic nucleus (STN). Eleven Parkinsonian patients received dexmedetomidine during deep brain stimulation surgery. Seven received continuous IV infusions during MER in the STN. The bispectral index (BIS) was used to estimate the level of consciousness. The quality of MER was evaluated as a function of BIS, clinical arousal, and dexmedetomidine dose. MER during wakefulness (BIS > 80; 0.1 to 0.4 mcg/kg/hr dexmedetomidine) was similar to the unmedicated state. Subthalamic MER was reduced when the patient was asleep or unarousable (BIS < 80). Anxiolysis persisted for hours. Arousal affects STN neurons. Dexmedetomidine “cooperative sedation,” from which the patient is easily aroused, provides interpretable STN MER and prolonged anxiolysis. We suggest dexmedetomidine infusions without a loading dose, a relatively low infusion rate, and discontinuation after completion of the bur holes.

132 A Randomized, Sham-Controlled Trial of Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Trial for the Treatment of Tremor-Dominant, Idiopathic Parkinson Disease.

INTRODUCTION Traditional stereotactic radiofrequency thalamotomy has been used with success in medication-refractory tremor-dominant Parkinson disease (PD). Recently, transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been used to successfully perform thalamotomy for essential tremor. We designed a double-blinded, randomized controlled trial to investigate the effectiveness of MRgFUS thalamotomy in tremor-dominant PD. METHODS Patients with medication-refractory, tremor-dominant PD were enrolled in the 2-center study and randomly assigned 1:2 to receive either a sham procedure or treatment. After the 3-month blinded phase, the sham group was offered treatment. Outcome was measured with blinded Clinical Rating Scale for Tremor (CRST) and Unified Parkinsons Disease Rating Scale (UPDRS) ratings. The primary outcome compared improvement in hand tremor between the treatment and sham procedure at 3 months. Secondary outcomes were measured with UPDRS and hand tremor at 12 months. Safety was assessed with MRI, adverse events, and comprehensive neurocognitive assessment. RESULTS Twenty-seven patients were enrolled and 6 were randomly assigned to a sham procedure. For the primary outcome assessment, there was a mean 50% improvement in hand tremor from MRgFUS thalamotomy at 3 months compared with a 22% improvement from the sham procedures (P = .088). The 1-year tremor scores for all 19 patients treated with 1-year follow-up data (blinded and unblinded) showed a reduction in tremor scores of 40.6% (P = .0154) and a mean reduction in medicated UPDRS motor scores of 3.7 (32%, P = .033). Sham patients had a notable placebo effect with a mean 21.5% improvement in tremor scores at 3 months. Twenty-seven patients completed the primary analysis, 19 patients completed the 12-month assessment, 3 patients opted for deep brain stimulation, 3 were lost to follow-up, 1 patient opted for no treatment, and 1 is pending a 12-month evaluation. CONCLUSION Transcranial MRgFUS demonstrates a trend toward improvement in hand tremor, and a clinically significant reduction in mean UPDRS. A significant placebo response was noted in the randomized trial.cause of intractable epilepsy in children. Seizure freedom following resection of FCD is determined by complete resection of the dysplastic cortical tissue.However, difficulty with intraoperative identification of the FCD lesion may limit the ability to achieve the surgical objective of complete extirpation of these lesions. The use of intraoperative magnetic resonance imaging (iMRI) may aid in real-time detection of these lesions and improve seizure control outcomes compared with traditional resective surgery.

Safety and Efficacy of Focused Ultrasound Thalamotomy for Patients With Medication-Refractory, Tremor-Dominant Parkinson Disease: A Randomized Clinical Trial

Importance Clinical trials have confirmed the efficacy of focused ultrasound (FUS) thalamotomy in essential tremor, but its effectiveness and safety for managing tremor-dominant Parkinson disease (TDPD) is unknown. Objective To assess safety and efficacy at 12-month follow-up, accounting for placebo response, of unilateral FUS thalamotomy for patients with TDPD. Design, Setting, and Participants Of the 326 patients identified from an in-house database, 53 patients consented to be screened. Twenty-six were ineligible, and 27 were randomized (2:1) to FUS thalamotomy or a sham procedure at 2 centers from October18, 2012, to January 8, 2015. The most common reasons for disqualification were withdrawal (8 persons [31%]), and not being medication refractory (8 persons [31%]). Data were analyzed using intention-to-treat analysis, and assessments were double-blinded through the primary outcome. Interventions Twenty patients were randomized to unilateral FUS thalamotomy, and 7 to sham procedure. The sham group was offered open-label treatment after unblinding. Main Outcomes and Measures The predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor subscore from the Clinical Rating Scale for Tremor (CRST). Secondary outcomes included descriptive results of Unified Parkinson’s Disease Rating Scale (UPDRS) scores and quality of life measures. Results Of the 27 patients, 26 (96%) were male and the median age was 67.8 years (interquartile range [IQR], 62.1-73.8 years). On-medication median tremor scores improved 62% (IQR, 22%-79%) from a baseline of 17 points (IQR, 10.5-27.5) following FUS thalamotomy and 22% (IQR, −11% to 29%) from a baseline of 23 points (IQR, 14.0-27.0) after sham procedures; the between-group difference was significant (Wilcoxon P = .04). On-medication median UPDRS motor scores improved 8 points (IQR, 0.5-11.0) from a baseline of 23 points (IQR, 15.5-34.0) following FUS thalamotomy and 1 point (IQR, −5.0 to 9.0) from a baseline of 25 points (IQR, 15.0-33.0) after sham procedures. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (4 events [20%]), finger paresthesia (1 event [5%]), and ataxia (1 event [5%]). Conclusions and Relevance Focused ultrasound thalamotomy for patients with TDPD demonstrated improvements in medication-refractory tremor by CRST assessments, even in the setting of a placebo response. Trial Registration ClinicalTrials.gov identifier NCT01772693

The use of magnetic resonance-guided high intensity focused ultrasound to treat essential tremor

Advances in ultrasound transducer technology have enabled for transcranial sonication with energy levels adequate to achieve tissue ablation. With MR-guidance and monitoring, precise lesioning is now possible of deep brain targets such as the thalamus and basal ganglia so that stereotactic lesioning is being reconsidered for the treatment of movement disorders. In this phase 1 clinical trial, we investigate the feasibility and safety of MRgFUS for performing a unilateral thalamotomy for medication-refractory essential tremor (ET). According to an FDA-approved protocol, 15 patients with medication-resistant ET underwent unilateral MRgFUS lesioning of the thalamus for dominant limb tremor. Intraprocedural monitoring was conducted with each incremental sonication using MR thermometry and clinical examination. Neurological assessments, validated tremor ratings, MRI, and quality of life data were recorded preoperatively and during a year post treatment. Adverse events were recorded throughout the study duratio...

Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor

Purpose To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET). Materials and methods Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment. Results The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = −0.929, −0.75, −0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post-treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = −0.719, −0.976, −0.707, −0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively). Conclusion Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy.