Background

Essential tremor (ET) is the most common movement disorder, with an estimated prevalence of between 0.3% and 5.55% of the population. In the USA there are about 10 million patients with ET. Physicians commonly view ET as a disease with a relatively benign clinical course, but specialists recognize its associated disabling aspects such as significant tremor of the hands which can result in functional impairment of eating, shaving, writing, doing house hold activities and functioning in the workplace.

The degree of tremor does not always correlate with the overall disability, and so the number of ET patients who may benefit from treatment is likely underestimated. 

Treatment

Treatment options include medication, lesioning procedures, and implantation of a deep brain stimulator, (DBS or “pacemaker”).

Medication is usually the first-line therapy, and most patients maintain a good quality of life with this treatment alone. However, up to 30% of ET patients do not respond to first-line medical therapy and may therefore consider surgical treatment options. (The 30% of patients who do not respond to drug therapy are called “medically refractory” ET patients.)

Lesioning for ET is a surgical procedure whereby the surgeon destroys a small volume of tissue in the brain by using either stereotactic radiosurgery or radiofrequency ablation. The neurosurgeon targets a small cluster of cells (a few mm in diameter) in the thalamus called the ventralis intermedius (VIM), which are causing the tremor. The procedure uses an anatomical atlas and some level of real-time imaging. In Radiofrequency ablation procedure it is also possible to get feedback from the patients (who are awake during treatment), to confirm targeting location. 

Lesioning on one side of the brain results in improvement of ET symptoms on the opposite side of the body. Treating both sides of the brain with lesioning procedure is not recommended due to high incidence of adverse effects.

The implantation of a deep brain stimulation device (DBS), or “pacemaker” is also used to treat ET. The neurosurgeon identifies the VIM nucleus in the brain and therein implants an electrode that delivers current. The surgeon then surgically implants a neurostimulator (pacemaker device) under the skin near the patient’s collar bone and subcutaneously connects the electrodes between the device and the VIM electrode. This procedure may then be repeated on the other side of the brain.

Focused Ultrasound treatment

Focused ultrasound is a completely noninvasive way to perform the lesioning procedure described above in the patient’s VIM. Using this treatment modality in conjunction with image guidance, the physician directs a focused beam of acoustic energy through the patient’s scalp, skull, and brain to precisely thermally coagulate the VIM, thereby destroying it without damaging nearby tissue or the tissues that the beam passes through on its way to the target.

Potential Benefits of Focused Ultrasound

The potential benefits of focused ultrasound for the treatment of ET are:

• It is a noninvasive, single treatment with a short recovery time and quick return to work and the activities of normal life (usually the next day).
• It has a reduce risk for infections, damage to non-targeted area and possibly even lower chance of post procedural blood clots formation.
• It offers rapid resolution of symptoms
• It does not use ionizing radiation

Because the treatment is noninvasive, focused ultrasound could be an option for medically refractory ET patients (those who do not respond well to medication) who do not want to undergo surgery.

Main Patient Selection Criteria for Focused Ultrasound treatment for ET

(Based on the criteria for trial participating)

• The patient has been diagnosed with ET as confirmed by clinical history and examination by a movement disorder neurologist.
• The patient experiences significant disability due to ET despite medical treatment 
• The ET is refractory to at least two medications, including either propranolol or primidone
• The patient has no evidence of cerebrovascular disease (multiple cerebrovascular accidents or a cerebrovascular accident within 6 months).
• The patient is not suspected of having idiopathic Parkinson disease. 
• The patient has not had previous brain surgery or a prior stereotactic ablation for treatment of ET.
• Because this procedure uses magnetic resonance imaging (MRI) for targeting, it is contraindicated in patients with MRI--related issues (e.g., the presence of metallic implants that are incompatible with MRI, sensitivity to MRI contrast agents, or the inability to fit into the MRI bore).

Clinical Trials

On Feb 25, 2011, physicians and researchers at the University of Virginia (UVA) in Charlottesville, VA, began a pilot clinical trial, and the first ET patient to be treated with focused ultrasound underwent the procedure. The 15th and final patient in that study was treated in December, 2011. Media coverage of this study is found below. Several more patients have undergone this treatment at The Center of Ultrasound Functional Neurosurgery in Solothurn, Switzerland.

Two clinical trials that are currently recruiting patients are underway in Canada and Switzerland (see details below), and a continuation study of 15 more patients is planned to begin at UVA in the next several months (details below).

University of Virginia, Charlottesville, Virginia, USA

Trial Status: first 15 patients enrollment completed, a continuation study planned to start in several months.

A pilot clinical trial was launched in February 2011 at the University of Virginia Medical Center, Charlottesville, VA, USA. Funded by the Focused Ultrasound Surgery Foundation and conducted under an FDA-approved protocol, the trial is evaluating the safety and initial efficacy of MRI-guided focused ultrasound in treating patients with ET.

Contact Information: Patient inquiries can be directed to the UVA Neurosurgery Clinical Trials department (Mrs. Johanna Loomba) at (434) 243-1435 or by emailing This e-mail address is being protected from spambots. You need JavaScript enabled to view it. . Due to the high volume of inquiries, email is recommended.  To submit yourself as a candidate for future focused ultrasound trials for ET, you can visit their online patient database https://www.healthsystem.virginia.edu/focusedultrasoundtrial.

Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Trial Status: Recruiting patients

The Focused Ultrasound Surgery Foundation is funding a pilot clinical trial to evaluate the feasibility and safety of MRI-guided focused ultrasound as a treatment for ET. Led by Michael Schwartz, MD, division head of Neurosurgery at Sunnybrook, this study is treating an area deep within the brain – the ventralis intermedius nucleus of the thalamus, known to be associated with movement disorders. The study is evaluating the mid-frequency version of the ExAblate Neuro, a transcranial system manufactured by Insightec, Ltd. of Israel. The ExAblate is the only focused ultrasound system currently on the market that has the capability to perform brain procedures. Performed under protocols approved by Health Canada, the noninvasive treatment administered through the awake patient’s intact skull requires no anesthesia. Six patients between the ages of 18 and 80 who have ET that is not controlled by medication are expected to be treated during the study. The Sunnybrook team will follow each patient’s progress for three months with follow-up contrast MRI and clinical examinations.

Contact Information: 

Karen Ng, Research Coordinator, Pager Number, 416-790-0809.

This study is open only to Canadians citizens.

The Center of Ultrasound Functional Neurosurgey, Solothurn, Switzerland 

Trial Status: Recruiting patients

Contact information: The Center of Ultrasound Functional Neurosurgery

Prof. Dr. med. Daniel Jeanmonod, M.D., (Principal Investigator) +41 32 621 79 32 or This e-mail address is being protected from spambots. You need JavaScript enabled to view it. .

Yonsei University Medical Center, Seoul, Korea 

Trial Status: Recruiting patients

Prof. Dr. Jin Woo Chang, M.D, Ph.D., (Principle investigator) Chair Department of Neurosurgery, Director Brain Research Institute

Contact information: Eun Jung Kweon, RN. MSN, Stereotactic & Functional Neurosurgery Coordinator

Tel: 82-2-2227-4578, Mobile : 82-17-282-1044, Fax: 82-2-393-9979

e-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it.

Regulatory Approval

Focused ultrasound treatment of ET is in the research stage. At this time, the United States Food and Drug Administration and Health Canada have only granted approval for its use in research as well as some other regulatory bodies worldwide.

Reimbursement

Treatment is currently available only as part of clinical research; therefore, procedures are free for patients who meet the inclusion criteria and elect to volunteer for the studies.

Patient Advocacy and online information

The International Essential Tremor Foundation provides global educational information, services, and support to those affected by essential tremor and to health care providers while promoting and funding ET research. See www.essentialtremor.org

Equipment Manufacturer

ExAblate Neuro InSightec LTD

http://www.insightec.com/ExAblate-Neuro.html

http://www.insightec.com/Essential_Tremor.html

 

Media coverage of the Pilot Essential Tremor Clinical Trial at the University of Virginia:

• January 23, 2012 ABC World News with Diane Sawyer “Sound Waves Cure Grandmother's Tremors”
• November 7, 2011 Video Interview with the 5th ET Study Patient, John Watterson, and his wife, Yvonne
• October 3, 2011 Press Release: Preliminary Study Results
• Sept. 13, 2011 Presentations from the UVA ET Support Group Event Given by the UVA Clinical Team (Neurosurgeon W. Jeffrey Elias, MD, Neurologic Physical Therapist Diane Huss, and Study Coordinator Johanna Loomba) and Patient #5, John Watterson
• June 13, 2011 Richmond Times Dispatch "Early Results of Essential Tremor Study Promising"
• April 12, 2011 Video Interview with the First ET Study Patient, Billy R. Williams
• March 11, 2011 Richmond Times Dispatch "U.Va. Uses Scalpel-free Brain Surgery to Treat Tremor"
• March 8, 2011 Video of Neurosurgeon W. Jeffrey Elias, MD describing the Focused Ultrasound Procedure for Essential Tremor
• March 2011 Focused Ultrasound Surgery Foundation Newsletter--the UVA Study

Notable Papers

As this is a new and procedure, and research is ongoing, no publication exists at this time on the use of Focused Ultrasound for the treatment of Essential tremor.

For technology overview and similar indication please see below:

1. Daniel Jeanmonod‚ Beat Werner‚ Anne Morel‚ Lars Michels‚ Eyal Zadicario‚ Gilat Schiff‚ Ernst Martin. Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. JNS, Neurosurgical Focus, 2012 32:E1, Jan 2012.

1. David Moser‚ Eyal Zadicario‚ Gilat Schiff‚ Daniel Jeanmonod. Measurement of targeting accuracy in focused ultrasound functional neurosurgery. JNS, Neurosurgical Focus, 2012 32:E2, Jan 2012

1. 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. 2010 Feb;66(2):323-32; discussion 332.

1. Martin E‚ Jeanmond D‚ Morel A‚ Zadicario E‚ Werner B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Annals of Neurology Volume 66, Issue 6, pages 858–861, December 2009

For reseach on other treatment modalities for Essential tremor, please see below:

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2. Binder DK, Rau GM, Starr PA: Risk Factors for Hemorrhage during Microelectrode-guided Deep Brain Stimulator Implantation for Movement Disorders.Neurosurgery 56:722-732, 2005

3. Cardoso F, Jankovic J, Grossman RG, Hamilton WJ: Thalamotomy for Dystonia and Hemiballismus. Neurosurgery 36:501-508, 1995

4. Chen HR, Heimburger RF, Lu CS, Cheng CS: [The stereotactic thalamotomy in parkinsonism]. Taiwan Yi Xue Hui Za Zhi 84:423-428, 1985

5. Constantoyannis C, Berk C, Honey CR, Mendez I, R.M. B: Reducing Hardware-Related Complications of Deep Brain Stimulation. Can J Neurol Sci 32:194-200, 2005

6. Fiacro Jiménez FV, José D. Carrillo-Ruiz, Luis García, Adrián, Madrigal ALV, Irma Márquez: Comparative Evaluation of the Effects of Unilateral Lesion versus Electrical Stimulation of the Globus Pallidus Internus in Advanced Parkinson's Disease. Stereotactic & Functional Neurosurgery 84:64-71, 2006

7. Fox MW, Ahlskog JA, Kelly PJ: Stereotactic ventrolateralis thalamotomy for medically refractory tremor in post-levodopa era Parkinson's disease patients. J Neurosurg 75:723-730, 1991

8. Fry WJ, Meyers R: Ultrasonic method of modifying brain structures. Confin Neurol 22:315-327, 1962

9. Gildenberg PL: Evolution of Basal Ganglia Surgery for Movement Disorders. Stereotactic and Functional Neurosurgery 84:131-135, 2006

10. Goldman MS, Kelly PJ: Symptomatic and functional outcome of stereotactic ventralis lateralis thalamotomy for intention tremor. J Neurosurg 77:223-229, 1992

11. Deep-Brain Stimulation for Parkinson's Disease Study Group: Deep brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. New England Journal of Medicine 345:956-963, 2001

12. Jagannathan J, Sanghvi NT, Crum LA, Yen CP, Medel R, Dumont AS, et al: High-intensity focused ultrasound surgery of the brain: part 1--A historical perspective with modern applications. Neurosurgery 64:201-210; discussion 210-201, 2009

13. Jankovic J, Cardoso F, Grossman RG, Hamilton WJ: Outcome after Stereotactic Thalamotomy for Parkinsonian, Essential, and Other Types of Tremor.Neurosurgery 37:680-687, 1995

14. Krayenbühl H, Wyss OAM, Yaşargil MG: Bilateral thalamotomy and pallidotomy as treatment for bilateral parkinsonism. J Neurosurg 18:429-444, 1961

15. Lim JY, DeSalles AA, Bronstein J, Masterman DL, Saver JL: Delayed internal capsule infarctions following radiofrequency pallidotomy. Report of three cases.J Neurosurg 87:955-960, 1997

16. Lindquist C, Kihlstrom L, Hellstrand E: Functional neurosurgery--a future for the gamma knife? Stereotact Funct Neurosurg 57:72-81, 1991

17. Meyers R: Current neurosurgical researches and treatment referable to the hyperkinetic disorders. N Y State J Med 62:2150-2167, 1962

18. 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 16:32-54, 1959

19. Nagaseki Y, Shibazaki T, Hirai T, Kawashima Y, Hirato M, Wada H, et al: Long-term follow-up results of selective VIM-thalamotomy. J Neurosurg 65:296-302, 1986

20. Pahwa R, Lyons KE, Wilkinson SB, Tröster AI, Overman J, Kieltyka J, et al: Comparison of Thalamotomy to Deep Brain Stimulation of the Thalamus in Essential Tremor. Movement Disorders 16:140-143, 2001

21. Paluzzi AA, Belli AP, Bain P, Liu X, Aziz TM: Operative and hardware complications of deep brain stimulation for movement disorders. Brit J Neurosurg 20:290-295, 2006

22. Rezai AR, Machado AG, Deogaonkar M, Azmi H, Kubu C, Boulis NM: Surgery for Movement Disorders. Neurosurgery 62:SHC 809-839, 2008

23. Schuurman PR, Bosch DA, Bossuyt PMM, Bonsel GJ, Van Someren EJW, De Bie RMA, et al: A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. New England Journal of Medicine 342:461-468, 2000

24. Tasker RR: The outcome of thalamotomy for tremor, in Textbook of Stereotactic & Functional Neurosurgery. New York: McGraw-Hill, 1998

25. Tasker RR: Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surgical Neurology 49:145, 1998

26. Terao T, Takahashi H, Yokochi F, Taniguchi M, Okiyama R, Hamada I: Hemorrhagic complication of stereotactic surgery in patients with movement disorders.J Neurosurg 98:1241-1246, 2003

27. Tomlinson FH, Jack CR, Kelly PJ: Sequential magnetic resonance imaging following stereotactic radiofrequency ventralis lateralis thalamotomy. J Neurosurg 74:579-584, 1991

28. Yoshor D, Hamilton WJ, Ondo W, Jankovic J, Grossman RG: Comparison of Thalamotomy and Pallidotomy for the Treatment of Dystonia. Neurosurgery 48:818-826, 2001