A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor W. Jeffrey Elias, M.D., Diane Huss, P.T., D.P.T., N.C.S., Tiffini Voss, M.D., Johanna Loomba, B.S., Mohamad Khaled, M.D., Eyal Zadicario, M.Sc., Robert C. Frysinger, Ph.D., Scott A. Sperling, Psy.D., Scott Wylie, Ph.D., Stephen J. Monteith, M.D., Jason Druzgal, M.D., Ph.D., Binit B. Shah, M.D., Madaline Harrison, M.D., and Max Wintermark, M.D. A bs tr ac t From the Departments of Neurosurgery (W.J.E., J.L., M.K., R.C.F., S.J.M.), Physical Therapy (D.H.), Neurology (T.V., S.A.S., S.W., B.B.S., M.H.), and Neuroradiology (J.D., M.W.), University of Virginia Health Sciences Center, Charlottesville; and In- Sightec, Haifa, Israel (E.Z.). Address reprint requests to Dr. Elias at the Department of Neurosurgery, University of Virginia, Box 8212, Charlottesville, VA 2298, or at wje4r@virginia.edu. N Engl J Med 213;369:64-8. DOI: 1.156/NEJMoa13962 Copyright 213 Massachusetts Medical Society. Background Recent advances have enabled delivery of high-intensity focused ultrasound through the intact human cranium with magnetic resonance imaging (MRI) guidance. This preliminary study investigates the use of transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor. Methods From February 211 through December 211, in an open-label, uncontrolled study, we used transcranial MRI-guided focused ultrasound to target the unilateral ventral intermediate nucleus of the thalamus in 15 patients with severe, medication-refractory essential tremor. We recorded all safety data and measured the effectiveness of tremor suppression using the Clinical Rating Scale for Tremor to calculate the total score (ranging from to 16), hand subscore (primary outcome, ranging from to 32), and disability subscore (ranging from to 32), with higher scores indicating worse tremor. We assessed the patients perceptions of treatment efficacy with the Quality of Life in Essential Tremor Questionnaire (ranging from to 1%, with higher scores indicating greater perceived disability). Results Thermal ablation of the thalamic target occurred in all patients. Adverse effects of the procedure included transient sensory, cerebellar, motor, and speech abnormalities, with persistent paresthesias in four patients. Scores for hand tremor improved from 2.4 at baseline to 5.2 at 12 months (P =.1). Total tremor scores improved from 54.9 to 24.3 (P =.1). Disability scores improved from 18.2 to 2.8 (P =.1). Quality-of-life scores improved from 37% to 11% (P =.1). Conclusions In this pilot study, essential tremor improved in 15 patients treated with MRIguided focused ultrasound thalamotomy. Large, randomized, controlled trials will be required to assess the procedure s efficacy and safety. (Funded by the Focused Ultrasound Surgery Foundation; ClinicalTrials.gov number, NCT ) 64 n engl j med 369;7 nejm.org august 15, 213

2 Essential tremor, the most common movement disorder, with a prevalence as high as 4%, is characterized by a rhythmic oscillation of agonist and antagonist muscle groups, typically between 8 and 12 Hz. 1 The cause of this disorder remains unknown, although there is often a familial component with a link to a particular polymorphism in the gene encoding leucine-rich repeat and immunoglobulin domain containing protein 1 (LINGO1). Although essential tremor is not medically dangerous, it is progressive and disabling in the home and workplace. 2 The degree of tremor does not always correlate with the severity of disability, 3 and patients with essential tremor often have lower perceived health status 4,5 and are at increased risk for social phobias 6 and depression. 7 Only a small proportion of such patients seek treatment. 6,7 Contemporary medical therapies are often successful, 8,9 but as many as 5% of patients with essential tremor cannot tolerate medications or have refractory, disabling tremor despite receiving the recommended doses of such medications. 1,11 The creation of lesions in the ventral intermediate nucleus of the thalamus or electrical stimulation of the same region, which is part of a large tremor circuit that integrates kinesthetic and proprioceptive sensory information from the cerebellum and spinal cord with the cerebral cortex, are effective surgical interventions for tremor, but many patients are reluctant to undergo such invasive surgeries. The use of ultrasound in the brain has been of interest for decades. Neuroscientists in the 195s attempted to use ultrasound to create lesions in brain structures, but such experiments were eventually abandoned because of the limitations of transcranial sonication and the need for a cranial window. 15 Ultrasound lesions that were produced through craniotomies were used to treat Parkinson s disease 16 and various psychiatric diseases. 17 Technological achievements in the past decade have enabled transcranial sonication through the intact human skull. Phased arrays of transducers and computed tomographic (CT) correction algorithms 22,23 facilitated the first transcranial sonications in patients with malignant glioma. 24 The creation of discrete focal lesions in subcortical structures was first used in the treatment of neuropathic pain syndromes. 25,26 The marriage of contemporary high-intensity ultrasound and magnetic resonance imaging (MRI) now allows for precise intracerebral targeting with real-time clinical and radiographic monitoring of the treatment location and intensity with the use of thermal imagery We present the results of a phase 1, open-label, uncontrolled study investigating transcranial MRI-guided focused ultrasound for the treatment of medication-refractory essential tremor. Me thods Patients From February 211 through December 211 at the University of Virginia, we enrolled 15 patients with severe, medication-refractory essential tremor. The diagnosis of essential tremor was confirmed by a neurologist specializing in movement disorders. A clinically significant tremor was defined as a score of more than 2 on the postural or action item on the Clinical Rating Scale for Tremor (ranging from to 4) 3 in the dominant hand, as well as substantial disability in the performance of at least two daily activities from the disability subsection of the scale. All patients provided written informed consent. Medication-refractory tremor was defined as persistent disabling tremor despite at least two trials of a full-dose therapeutic medication, one of which had to include propranolol or primidone. 8,9 Doses of medications were stable for 3 days before enrollment and then maintained without adjustment during the study. In each patient, the dominant hand was the most severely affected extremity and was targeted for treatment. Eligibility criteria excluded patients who had undergone previous stereotactic or cranial surgery or who had other neurodegenerative conditions (including Parkinson s disease), unstable cardiac conditions, or a coagulopathy. All patients were screened by a neuropsychologist for the legal capacity to provide informed consent and to exclude cognitive impairment (a score of >24 [out of total score of 3] on the Mini Mental State Examination), a history of psychiatric disease, or previous evidence of substance abuse. Patients also underwent ultrasonography of the legs to rule out the presence of deep-vein thrombosis. n engl j med 369;7 nejm.org august 15,

3 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Outcome Assessments Study Visits Clinical assessments were performed by a movement-disorder neurologist and a physical therapist with a neurologic specialty. As study investigators, these clinicians were aware of the goals of the study and whether patients were being evaluated before or after treatment. Patients were assessed at baseline and at 1 day, 1 week, 1 month, 3 months, and 12 months after treatment. Efficacy Tremor was assessed throughout the study by the same investigator on the basis of the Clinical Rating Score for Tremor, which provides a validated quantification of the severity of essential tremor. Three subsections of the scale (A, tremor; B, tasks; and C, disability) contribute to a maximum score of 16 points, with higher scores indicating more severe tremor. The hand subscore served as the primary clinical end point derived by summing eight items that evaluate hand tremor and ability to perform tasks (ranging from to 32, with higher scores indicating more severe tremor). Secondary measures included the change in total Clinical Rating Score for Tremor and the self-reported Quality of Life in Essential Tremor Questionnaire (ranging from to 1%, with higher scores indicating greater perceived disability). 31 Functional improvement was determined on the basis of the disability score (ranging from to 32, with higher scores indicating more disability), as well as on the Physical Performance Test (ranging from to 32, with higher scores indicating better performance). 32 Safety Adverse events were categorized as being specifically associated with the thalamotomy procedure, the use of a stereotactic head frame during the procedure, ultrasound sonication, or MRI. A complete neurologic and physical examination was performed by a movement-disorder neurologist at each study visit, and clinically relevant changes were reported as adverse events. In addition, quantitative measures of neurologic function were recorded by a physical therapist with a neurologic specialty, including grip strength (as measured on dynamometry), manual muscle testing, sensory testing with Semmes Weinstein monofilaments, two-point discrimination and vibratory measurements, screening for dysarthria, single-leg stance for balance, gait velocity, and the Dynamic Gait Index (ranging from to 24, with higher scores indicating more gait stability). 33 MRI was performed at each study visit through 3 months and included the following sequences: T 1 - and T 2 -weighted imaging, fluidattenuated inversion recovery (FLAIR), susceptibility-weighted imaging, diffusion-weighted imaging, and T 1 -weighted imaging with gadolinium. Focused Ultrasound Thalamotomy On the treatment day, patients presented to the focused-ultrasound suite, where a stereotactic head frame was affixed to the shaved head with the use of a local anesthetic. An elastic diaphragm was attached to the scalp and connected to the ultrasound transducer so that it could be filled with chilled, degassed water. Patients were then transferred into the bore of the magnet for the treatment. Sedatives were not administered, but an anesthesiologist maintained normal blood pressure throughout the procedure. The procedure was performed in an MRIguided focused ultrasound system, consisting of a 3 Tesla MRI (GE) and the ExAblate Neuro (InSightec), which includes a hemispheric, 65-kHz, 124-element, phased-array transducer. A reference scan was performed to position the transducer to the target. A series of anatomical MRI scans were fused to the preoperative CT scan for the skull-correction algorithm. Traditional stereotactic planning was performed for the ventral intermediate thalamus as three quarters of the length of the anterior posterior commissural line and 14 to 15 mm lateral of midline or 11 mm from the third ventricle wall in cases of ventriculomegaly. After treatment planning, a series of lowpower sonications (typically, 15 to 25 W) that produced temperatures of 4 to 45 C confirmed accurate focusing in three orthogonal planes by means of magnetic resonance (MR) thermography. Therapeutic sonications of 1 to 2 seconds were then implemented by gradually escalating the power and monitoring the temperature. All patients communicated freely with the clinicians throughout the treatment. Clinical assessments for tremor suppression and for the presence of any side effects were performed after each sonication. During the procedure, patients were asked to manually draw 642 n engl j med 369;7 nejm.org august 15, 213

4 a series of spirals, and neurologic examinations were performed for sensation, speech, and motor strength. This protocol was continued until tremor suppression was observed (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Final sonication temperatures ranged from 55 to 63 C at the maximal voxel measured by means of MR thermography. 34,35 At the completion of the procedure, the frame was removed and the patient was observed overnight in the neurologic intensive care unit. Patients were discharged the next day. Study Oversight The study was conceived and conducted by the investigators at the University of Virginia, who collected and analyzed all the data. All authors had access to the data and vouch for its accuracy and for the fidelity of this report to the study protocol (available at NEJM.org). The first author wrote the first draft of the manuscript and made the decision to submit the manuscript for publication. All financial support was provided by the Focused Ultrasound Surgery Foundation. InSightec, the maker of the focused ultrasound system used in this study, provided technical assistance for all the treatments and made financial contributions to the Focused Ultrasound Surgery Foundation. InSightec representatives were responsible for obtaining regulatory approvals and for compliance with Food and Drug Administration regulations, including monitoring and proper conduct of the study. Statistical Analysis We performed the nonparametric Friedman test to determine the primary outcome (change in hand tremor score) and secondary outcomes (scores on the total and disability subsections of the Clinical Rating Score for Tremor, the Dynamic Gait Index, grip strength, Physical Performance Test, and its simulated eating task) across five study visits at baseline before treatment and at 1 week, 1 month, 3 months, and 12 months after treatment. The primary efficacy analysis, as specified in the original protocol, was the change in hand tremor score between baseline and 3 months, but in this report we present data at 12 months to better assess the durability of treatment. We used the nonparametric Wilcoxon test for two related samples to evaluate differences Table 1. Characteristics of the 15 Patients.* Characteristic Value Age yr 66.6±8. Male sex no. (%) 1 (67) Right-handedness no. (%) 12 (8) Associated peripheral neuropathy no. (%) 2 (13) Baseline tremor score on CRST 54.9±14.4 Duration of tremor yr 32.±21.3 No. of previous medications received 2.7±1.1 Family history of tremor no. (%) >2 Family members 9 (6) 2 Family members 3 (2) Family members 3 (2) Alcohol-responsive tremor no. (%) Yes 6 (4) No 3 (2) Uncertain 6 (4) * Plus minus values are means ±SD. Total scores on the Clinical Rating Scale for Tremor (CRST) range from to 16. between values at baseline and at each of the four assessments after treatment, as well as differences in scores over time. R esult s Patients The 15 study patients had a mean (±SD) age of 66.6±8. years (range, 53 to 79) and had a mean history of tremor of 32.±21.3 years (range, 4 to 6). Most of the patients were male (67%) and right-handed (8%), with a positive family history of tremor (8%) (Table 1). Six patients reported a beneficial tremor response after the consumption of one or two alcoholic drinks. Two patients had peripheral neuropathy at baseline. The mean baseline score on the Clinical Rating Scale for Tremor was 54.9±14.4. All tremors had been medically resistant to trials of a median of 2 medications (range, 2 to 5). Tremor There was significant improvement in tremor in the contralateral hand, as measured on the Clinical Rating Scale for Tremor, from a mean baseline score of 2.4±5.2 to a score of 4.3±3.5 at 3 months and 5.2±4.8 at 12 months (a relative n engl j med 369;7 nejm.org august 15,

5 T h e n e w e ngl a nd j o u r na l o f m e dic i n e A Hand Tremor (group) 25 2 Contralateral Ipsilateral B Hand Tremor (individual) CRST Score CRST Score Baseline 1 Wk 1 Mo 3 Mo 1 Yr Baseline Before Treatment Day After Treatment Day 1 Wk 1 Mo 3 Mo 1 Yr C Total Tremor CRST Score Baseline 1 Wk 1 Mo 3 Mo 1 Yr E Simulated Eating Task 4 D Disability CRST Score Baseline 1 Wk 1 Mo 3 Mo 1 Yr F Quality of Life 5 Seconds QUEST Score Baseline 1 Wk 1 Mo 3 Mo 1 Yr Baseline 3 Mo 1 Yr Figure 1. Improvement in Tremor, Disability, Physical Performance, and Quality of Life. Among 15 patients who underwent unilateral transcranial MRI-guided focused ultrasound thalamotomy for the treatment of essential tremor, the greatest degree of tremor improvement was observed in the contralateral hand, as shown by hand-tremor subscores (ranging from to 32) derived from the Clinical Rating Scale for Tremor (CRST, ranging from to 16) (Panel A). In contrast, there was almost no change in the untreated, ipsilateral hand. Results for individual patients show the evolution of tremor improvement immediately after the procedure, which was maximal during the first week with the onset of perilesional edema and then stabilizing for 13 of the 15 patients during the next 12 months (Panel B). Mean total tremor scores improved to a lesser degree than hand-tremor scores because of partial treatment effects on axial tremors and the lack of effect in the ipsilateral, appendicular regions (Panel C). After treatment, patients reported almost no residual limitations from tremor, as measured on the disability subsection of the CRST (Panel D). Clinically significant functional improvements in performance were quantified on the simulated eating task of the Physical Performance Test (Panel E). Patients self-perception of their condition improved on the Quality of Life in Essential Tremor Questionnaire (QUEST) (Panel F). T bars represent standard errors. reduction of 75% from baseline to 12 months, P =.1) (Fig. 1). There was also significant improvement in total tremor scores, from 54.9±14.4 at baseline to 24.3±14.8 at 12 months (P =.1), a relative reduction of 56%. In contrast, there was no significant difference in the tremor score for the ipsilateral hand from baseline to 12 months (13.4±5.2 vs. 13.5±6.3, P =.9). Among 1 patients who had axial tremor, there was improvement of at least 2 points in 6 patients, with no worsening of tremor, with mean changes ranging from 2.3 to 2.7 points (on a scale of n engl j med 369;7 nejm.org august 15, 213

6 points) (P =.26). Five of nine vocal tremors improved partially but were not quantified with statistical analysis. Individual tremor scores and writing samples are provided in Tables S1 and S2 and Figure S2 in the Supplementary Appendix. Disability, Quality of Life, and Physical Performance During the first year after treatment, there was significant improvement in the mean score on the disability subsection of the Clinical Rating Scale for Tremor, from 18.2±4.1 at baseline to 2.8±3.4 at 12 months (P =.1), for a relative reduction of 85%. Patients perceptions of their quality of life on the Quality of Life in Essential Tremor Questionnaire also improved significantly (37% vs. 12%, P =.1). And there was significant improvement in the mean score on the Physical Performance Test from baseline to 12 months (22.9±3. to 27.1±2.7, P =.1), including an improvement in the score for the simulated eating task, from 29.4±1.8 seconds to 11.6±3.3 seconds (P =.1). Four patients who could not perform the simulated eating task preoperatively because of severe tremor accomplished it within normal time limits after treatment (mean, 12.3 seconds) (Fig. 1). Adverse Events The most common side effects were paresthesias of the face or fingers, presumably because of involvement of the sensory, ventroposterolateral thalamus adjacent to the ventral intermediate nucleus (Table 2). Four patients had persistent paresthesias. One of these patients had a persistent dysesthesia of his dominant index finger that remained uncomfortable despite trials of gabapentin and pregabalin. Five patients reported temporary unsteadiness without objective change on the neurologic examination. Four others had objective decline in the Dynamic Gait Index and were classified as having ataxia at 1 week, with complete resolution at 1 month (Table S3 in the Supplementary Appendix). A single patient reported having grip weakness for 5 days, although results on dynamometry were unchanged at 1 week after treatment. There was no other decline in quantitative measures of neurologic function. Four patients reported occipital numbness, which was presumably caused by low placement of the frame pins at the greater occipital nerve. A brief syncopal event occurred in one patient Table 2. Adverse Events Reported in the 15 Patients. Event Transient At 12 Months no. of patients Related to thalamotomy Paresthesia Lip or tongue 9 2 Finger 5 1 Dysesthesia of index finger 1 1* Unsteady feeling 5 Ataxia (<1 month) 4 Dysmetria (<1 month) 1 Weak grip (5 days) 1 Slurred speech (1 day) 1 Related to use of stereotactic frame Headache >1 day 4 Scalp numbness in occipital region 4 Pin-site laceration 1 Periorbital edema 1 Related to sonication Head pain 9 Flushed or warm sensation 4 Tilting, falling, or spinning sensation 5 Light-headedness 6 Nausea 5 Emesis 3 Syncope 1 Related to MRI Scalp burn from pin-site heating 2 * Dysesthesia of the index finger was the only serious adverse event reported during the study. Sonication-related side effects were defined as those that occurred only during the 1 to 2 seconds of sonication and immediately resolved. during treatment, but postoperative imaging and cardiac evaluation were negative. Two patients had small, first-degree burns at pin sites, which probably occurred from MR heating of aluminum pins intended to reduce MR artifact. Radiologic Assessments The lesions were nearly undetectable on MRI T 1 - weighted sequences until 24 hours after treatment, but hyperacute lesions could be detected on T 2 - and diffusion-weighted imaging (Fig. 2). Perilesional edema, as seen on T 2 -weighted imaging and FLAIR, peaked at 1 week and resolved n engl j med 369;7 nejm.org august 15,

7 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Baseline 1 Day 1 Week 1 Month 3 Months T 1 T 2 DWI SWI Figure 2. Magnetic Resonance Imaging in a Patient with Essential Tremor before and after Treatment. The patient was treated with transcranial MRI-guided focused ultrasound to create a lesion in the left ventral intermediate nucleus of the thalamus. The lesions were nearly undetectable on T 1 -weighted sequences until 24 hours after treatment. On T 2 -weighted imaging, three concentric zones at the site of the lesion are apparent: a hypointense zone I at the center, a hyperintense zone II demarcated by a hypointense rim, and a slightly hyperintense zone III at the periphery. Zone II, which corresponds to vasogenic edema, is typically seen at 24 hours and at 1 week and then resolves. Zones I and II evolved into a round cavity in which diffusion-weighted imaging (DWI) showed restriction by 24 hours after treatment. Diffusion pseudonormalized at 1 month, when the cavity collapsed. No major intracranial hemorrhage occurred at any time point, but blood products responsible for hypointensity on susceptibilityweighted imaging (SWI) were seen within zones I and II at all time points. at 1 month. As such, mean lesion volume was maximal at 1 week. The lesion collapsed by 1 month in 12 patients and by 3 months in 3 patients and became difficult to detect afterward. Overt intracerebral hemorrhage did not occur, but hypointense signal at the lesion suggestive of degraded blood products was evident on susceptibility-weighted imaging throughout the study. The accuracy in lesion creation was determined from image fusion of each preoperative target, with the 1-day and 1-week postoperative lesion depicted on T 1 - and T 2 -weighted sequenc- 646 n engl j med 369;7 nejm.org august 15, 213

8 es. The lesion placement was most precise in the lateral and anteroposterior dimensions, with mean error distances of.1±.9 mm and.±.9 mm, respectively. The mean error in the dorsal ventral dimension was 2.2±2.4 mm and probably reflects the learning curve with single-slice MR thermography. Sonication Measures Sonications (mean number, 17.9±4.6; range, 11 to 26) were started at very low energies for system calibration, with escalation toward a more therapeutic and ablative temperature. Final sonication energies of 1,32±4537 J (range, 65 to 2,8) produced a mean maximal temperature voxel of 58.5±2.5 C (range, 54 to 63) in the lesion. Neuromodulation and Brain Mapping Four patients reported neurologic symptoms during the treatment, which allowed for refinement of the target by refocusing the transducer. All four noted paresthesias of the lips or fingers and never showed motor deficits, suggesting involvement of the ventroposterolateral nucleus and not the internal capsule. Anterior adjustments of the transducer focus were made during the incremental titration of acoustic power toward a therapeutic temperature, but one patient had persistent sensory symptoms in his index finger as the maximal temperature voxel reached 48 C during a sonication of 55 W for 12 seconds. The other three patients had no clinically significant alteration in sensation. Tremor suppression tended to begin at temperatures of approximately 5 C. Initially, postural tremor was transiently suppressed for seconds during sonication. More permanent relief of postural and action tremor occurred after subsequent sonications with higher energies. Of the 12 patients whose tremors had a postural component, that aspect always resolved before improvement in action tremor. Discussion In this pilot study involving 15 patients with essential tremor who were followed for 1 year after treatment, thalamotomy was achieved with transcranial MRI-guided focused ultrasound. Unilateral thalamotomy improved tremor in the contralateral, dominant hand and overall tremor, as measured on a validated tremor-rating scale. Patients reported improvements in tremor-related quality of life after the procedure. Stereotactic procedures such as radiofrequency thalamotomy and deep-brain stimulation have been shown to be effective for the treatment of essential tremor ,36 Stereotactic radiosurgery has also been used to perform thalamotomy for tremor but with latent effects occurring months after treatment Such procedures have been associated with serious adverse events, including intracerebral hemorrhage and neurologic impairment (e.g., hemiparesis, ataxia, and dysarthria). Similar adverse events may result from focused ultrasound thalamotomy. One serious adverse event occurred in our study as a persistent dysesthesia in the dominant index finger. We observed other sensory and cerebellar side effects that were consistent with the extension of the thalamic lesion beyond the target. On MRI, small foci of susceptibilityweighted signal intensity were present at the site of the lesions. Our study has several limitations. We did not perform comprehensive cognitive assessments, and it is possible that focused ultrasound thalamotomy caused cognitive impairment. The study did not include a control group and did not provide information about the efficacy of this procedure as compared with other treatments. Investigators and patients were all aware of treatments that were performed, which may have introduced bias in favor of reporting improvements in symptoms and quality of life. Blinded, randomized trials are needed to assess the effectiveness of the treatment and durability of benefits, and direct comparisons with currently available therapies are needed. Studies with larger sample sizes are needed to assess for infrequent but serious adverse events, such as intracranial hemorrhage and permanent neurologic impairment. Supported by the Focused Ultrasound Surgery Foundation. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Karen Osteen, R.N., Kathy Maynard, R.N., Bob Davis, N.P., and Caroline Metsch, P.A., for providing clinical assistance; Thomas Huerta, M.D., and Prashant Raghavan, M.D., for providing imaging assistance; and Sean McKisic, M.D., for preparing Figure S1 in the Supplementary Appendix. n engl j med 369;7 nejm.org august 15,

9 References 1. Louis ED, Ottman R, Hauser WA. How common is the most common adult movement disorder? Estimates of the prevalence of essential tremor throughout the world. Mov Disord 1998;13: Koller W, Biary N, Cone S. Disability in essential tremor: effect of treatment. Neurology 1986;36: Heroux ME, Parisi SL, Larocerie- Salgado J, Norman KE. Upper-extremity disability in essential tremor. Arch Phys Med Rehab 26;87: Woods SP, Scott JC, Fields JA, Poquette A, Troster AI. Executive dysfunction and neuropsychiatric symptoms predict lower health status in essential tremor. Cog Behav Neurol 28;21: Lorenz D, Schwieger D, Moises H, Deuschl G. Quality of life and personality in essential tremor patients. Mov Disord 26;21: Schneier FR, Barnes LF, Albert SM, Louis ED. Characteristics of social phobia among persons with essential tremor. J Clin Psych 21;62: Louis ED, Barnes L, Albert SM, et al. Correlates of functional disability in essential tremor. Mov Disord 21;16: Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 25; 64: Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology. Neurology 211;77: Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in essential tremor. Neurology 1989;39: Diaz NL, Louis ED. Survey of medication usage patterns among essential tremor patients: movement disorder specialists vs. general neurologists. Parkinsonism Relat Disord 21;16: Tasker RR. Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg Neurol 1998;49: Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med 2;342: Anderson VC, Burchiel KJ, Hart MJ, Berk C, Lou JS. A randomized comparison of thalamic stimulation and lesion on self-paced finger movement in essential tremor. Neurosci Lett 29;462: Fry WJ, Mosberg WH Jr, Barnard JW, Fry FJ. Production of focal destructive lesions in the central nervous system with ultrasound. J Neurosurg 1954;11: Meyers R, Fry WJ, Fry FJ, Dreyer LL, Schultz DF, Noyes RF. Early experiences with ultrasonic irradiation of the pallidofugal and nigral complexes in hyperkinetic and hypertonic disorders. J Neurosurg 1959;16: Nelson E, Lindstrom PA, Haymaker W. Pathological effects of ultrasound on the human brain: a study of 25 cases in which ultrasonic irradiation was used as a lobotomy procedure. J Neuropathol Exp Neurol 1959;18: Hynynen K, Clement GT, McDannold N, et al. 5-Element ultrasound phased array system for noninvasive focal surgery of the brain: a preliminary rabbit study with ex vivo human skulls. Magn Reson Med 24;52: Clement GT, White J, Hynynen K. Investigation of a large-area phased array for focused ultrasound surgery through the skull. Phys Med Biol 2;45: Sun J, Hynynen K. The potential of transskull ultrasound therapy and surgery using the maximum available skull surface area. J Acoust Soc Am 1999;15: Hynynen K, Jolesz FA. Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol 1998;24: Aubry JF, Tanter M, Pernot M, Thomas JL, Fink M. Experimental demonstration of noninvasive transskull adaptive focusing based on prior computed tomography scans. J Acoust Soc Am 23;113: Clement GT, Hynynen K. A non-invasive method for focusing ultrasound through the human skull. Phys Med Biol 22;47: McDannold N, Clement GT, Black P, Jolesz F, Hynynen K. Transcranial magnetic resonance imaging-guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 21; 66: Jeanmonod D, Werner B, Morel A, et al. Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus 212;32(1):E Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol 29;66: Cline HE, Schenck JF, Watkins RD, Hynynen K, Jolesz FA. Magnetic resonance-guided thermal surgery. Magn Reson Med 1993;3: De Poorter J, De Wagter C, De Deene Y, Thomsen C, Stahlberg F, Achten E. Noninvasive MRI thermometry with the proton resonance frequency (PRF) method: in vivo results in human muscle. Magn Reson Med 1995;33: Ishihara Y, Calderon A, Watanabe H, Okamoto K, Suzuki Y, Kuroda K. A precise and fast temperature mapping using water proton chemical shift. Magn Reson Med 1995;34: Stacy MA, Elble RJ, Ondo WG, Wu SC, Hulihan J. Assessment of interrater and intrarater reliability of the Fahn-Tolosa- Marin Tremor Rating Scale in essential tremor. Mov Disord 27;22: Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord 25;11: Reuben DB, Siu AL. An objective measure of physical function of elderly outpatients: the Physical Performance Test. J Am Geriatr Soc 199;38: Shumway-Cook A, Woollacott M. Motor control: theory and practical applications. Baltimore: Williams & Wilkins, McDannold N, Vykhodtseva N, Jolesz FA, Hynynen K. MRI investigation of the threshold for thermally induced bloodbrain barrier disruption and brain tissue damage in the rabbit brain. Magn Reson Med 24;51: Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol Biol Phys 1984;1: Pahwa R, Lyons KE, Wilkinson SB, et al. Comparison of thalamotomy to deep brain stimulation of the thalamus in essential tremor. Mov Disord 21;16: Young RF, Li F, Vermeulen S, Meier R. Gamma knife thalamotomy for treatment of essential tremor: long-term results. J Neurosurg 21;112: Lim SY, Hodaie M, Fallis M, Poon YY, Mazzella F, Moro E. Gamma knife thalamotomy for disabling tremor: a blinded evaluation. Arch Neurol 21;67: Kooshkabadi A, Lunsford LD, Tonetti D, Flickinger JC, Konziolka D. Gamma knife thalamotomy for tremor in the magnetic resonance imaging era. J Neurosurg 213;118: Copyright 213 Massachusetts Medical Society. clinical problem-solving series The Journal welcomes submissions of manuscripts for the Clinical Problem-Solving series. This regular feature considers the step-by-step process of clinical decision making. For more information, please see authors.nejm.org. 648 n engl j med 369;7 nejm.org august 15, 213