Essential Tremor

Focused ultrasound treatment for Essential Tremor has been approved by the Food and Drug Administration (FDA) in July 2016.

Clinical Key

Essential tremor (ET) is the most common movement disorder, affecting an estimated 3% of the population, or approximately 10 million individuals in the United States. ET is commonly viewed as a relatively benign disease.

However, the associated disabling aspects of ET, such as significant tremor of the hands, can impair patients’ ability to eat, shave, write, perform household activities, and function in the workplace.

The underlying etiology of ET is unclear, but cases often run in families (familial tremor). It has been estimated that approximately 50% of all cases are due to a genetic mutation, and the pattern of inheritance is most consistent with autosomal dominant transmission (i.e. dominant trait).

Current Treatment

Treatment options for ET include medication, thalamotomy procedures in which a predefined small volume of brain tissue containing nerve cells causing the tremor is destroyed, and deep brain stimulation (DBS) in which a stimulator (i.e. “pacemaker”) generates mild electrical currents through an electrode implanted in the brain.

Medication
Medication is typically the first line therapy for ET, and most patients maintain a good quality of life with this treatment alone. However, up to 30% of ET patients do not respond to medication and may therefore be considered as candidates for surgical treatment. Because the degree of tremor does not always correlate with the overall disability, the number of ET patients who may have significant disability and are refractory to medication is likely underestimated.

NEJM ET video320 captionThalamotomy
Thalamotomy for ET is a surgical procedure involving the use of either stereotactic radiosurgery or radiofrequency (RF) ablation to destroy a small volume of tissue in the thalamus, an area deep within the brain. These treatments target the ventralis intermedius (VIM), a small cluster of cells in the thalamus—only a few millimeters in diameter—that is known to cause the tremor. The target is determined anatomically and identified and delineated on the patient’s MRI scans. During RF ablation procedures, patients remain awake and provide feedback to confirm the targeted location. The physicians use electrical stimulation to generate this patient feedback. After feedback confirms the target, the neurosurgeon performs the ablation—lesion formation—by heating the tissue with radiofrequency energy. Ablation on one side of the brain improves symptoms on the opposite side of the body. Ablation on both sides of the brain is not recommended because it may lead to speech disturbances.

Deep Brain Stimulation
For this procedure, a burr hole is created in the skull to enable insertion of a DBS electrode into the thalamus. The electrode is connected to a neurostimulator (pacemaker device) that is permanently implanted under the skin near the patient’s collar bone. The electrode delivers a low level electrical current to affect the tissue surrounding the DBS electrode’s tip in the VIM nucleus. DBS can be performed on both sides of the brain without the complications of ablation as noted above.

Focused Ultrasound Treatment

Focused ultrasound is a completely non-invasive method of thalamotomy (as described above) that could be an effective option for certain patients. Focused ultrasound is performed while the patient is awake and involves no anesthesia, no incisions in the scalp, and no burr holes through the skull or insertion of electrodes into the brain. During focused ultrasound therapy, target cells in the thalamus are visualized in real time using MR imaging. The highly precise treatment uses focused beams of acoustic energy to heat and destroy target cells without harming adjacent tissue.

Most clinical studies with MR-guided Focused Ultrasound (MRgFUS) and essential tremor have targeted a region in the thalamus involving the Vim nucleus and were performed on only one side of the brain, for reasons noted under RF ablation above. Recent studies from Switzerland demonstrated safety and efficacy in targeting a different part of the thalamus called the cerebellothalamic tract (CTT), below the thalamus.  Three out of 21 patients in this study received treatments on both the right and left sides with no significant adverse events and had significant improvement clinically, thus raising the possibility of treating patients bilaterally. To learn more about the CTT approach see the Center for Ultrasound Functional Neurosurgery Solothurn website.

Focused ultrasound may offer the following benefits in treating ET: 

  • It is a non-invasive, single treatment that enables patients to recover rapidly and quickly return to activities of normal life (usually the next day).
  • Compared to RF ablation or DBS, focused ultrasound offers a reduced risk of infection, of damage to the non-targeted area, and of blood clot formation.
  • Focused ultrasound offers rapid resolution of symptoms.
  • In contrast to lesioning performed with stereotactic radiosurgery, focused ultrasound does not use ionizing radiation, thus avoiding the side effects of exposure to radiation.
  • Because it is non-invasive, 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.

Clinical Trials

Phase 3 Pivotal Clinical Study
Enrollment has been completed in a multi-center pivotal randomized study to evaluate the safety and efficacy of focused ultrasound for the treatment of medication-refractory essential tremor patients. Results of this study have been reviewed and approved by the FDA. As this treatment transitions from clinical trials to commercial treatment, we will continue to list the clinical trials sites (below). Some may continue to offer treatments until the commercial care is available. 

A trial protocol is in place to support ongoing access for patients to this treatment at some of the original study sites. For further information, please contact the individuals below:

Ohio State Wexner Medical Center - Columbus, Ohio
Contact: Jennifer Herrick - (614) 685-4447 or

Stanford University Medical Center - Stanford, California
Contact:

Sunnybrook Health Sciences Centre - Toronto, Ontario, Canada
Contact: Maheleth Llinas - 416-603-5800 ext 6121  

Swedish Medical Center - Seattle, Washington
Contact: Amanda Brown - 206.320.2804

University of Maryland Medical System - Baltimore, Maryland
Contact: Andrea Reddick - 410-328-4723 

University of Virginia - Charlottesville, Virginia
Patient inquiries can be directed to the UVA Neurosurgery Clinical Trials division*
Contact: Johanna Loomba at 

*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 UVA’s online patient database at https://www.healthsystem.virginia.edu/focusedultrasoundtrial

Tokyo Women's Medical University (TWMU) - Tokyo, Japan
Contact: Miyoko Naganuma +81 (0)3-5269-7386

Treatment Sites

Please see a list of possible treatment sites here.

Regulatory & Reimbursement

The ExAblate system manufactured by Insightec earned FDA approval to treat essential tremor in July 2016. It is also approved for treating essential tremor in Europe, Korea and Canada.

In the US, Medicare, at a national level, allows payment, at a level of nearly $10,000. However, the regional payment centers for Medicare still need to approve the procedure for payment in that region, and we are not aware of any regions that are paying for this care at the present time. These regions are different for various parts of the country, so patients should inquire from their physician regarding the local regional decisions. Many centers are putting patients on a waiting list until they get confirmation that local payment status has been approved.

Although the code for this care (0398T) has been approved to move to the payable class, it will not transition to the updated codes until 2019. Until then, it is more likely that payment rejections will have to be appealed in order to ensure payment.

Commercial coverage and Medicaid will typically follow Medicare but should be evaluated with each company and region. Some facilities have a cash payment option, for those who are not willing to wait for insurance decisions for payment. Prices vary, but a rough estimate is $40,000.

Insightec has established an informational website, including patient stories and access to treatment site information. They have also set up a Reimbursement Support Manager, who can help with questions about the status of reimbursements. Her contact information is: Kim Martin, Reimbursement Support Manager, 1-(866) 392-8478 or .

Patient Advocacy

The International Essential Tremor Foundation provides global educational information, services, and support to those affected by ET and to healthcare providers. The Foundation also promotes and funds ET research.

Hope Netbased in northern Virginia, is working to raise awareness of ET.

APTES supports French-speaking ET patients, primarily in France, Belgium, Switzerland, and Quebec.

Tremor Action Network is a volunteer, nonprofit, public benefit organization founded by patients with essential tremor, cervical dystonia, Parkinson's disease, and tremor-related neurological movement disorders.

Notable Papers

Schlesinger D, Lee M, Ter Haar G, Sela B, Eames M, Snell J, Kassell N, Sheehan J, Larner J, Aubry JF. Equivalence of cell survival data for radiation dose and thermal dose in ablative treatments: analysis applied to essential tremor thalamotomy by focused ultrasound and gamma knife. Int J Hyperthermia. 2017 Jan 3:1-27. doi: 10.1080/02656736.2016.1278281.

Hughes A, Huang Y, Pulkkinen A, Schwartz ML, Lozano AM, Hynynen K. A numerical study on the oblique focus in MR-guided transcranial focused ultrasound. Phys Med Biol. 2016 Nov 21;61(22):8025-8043.

Jang C, Park HJ, Chang WS, Pae C, Chang JW. Immediate and Longitudinal Alterations of Functional Networks after Thalamotomy in Essential Tremor. Front Neurol. 2016 Oct 24;7:184.

Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, Schwartz M, Hynynen K, Lozano AM, Shah BB, Huss D, Dallapiazza RF, Gwinn R, Witt J, Ro S, Eisenberg HM, Fishman PS, Gandhi D, Halpern CH, Chuang R, Butts Pauly K, Tierney TS, Hayes MT, Cosgrove GR, Yamaguchi T, Abe K, Taira T, Chang JW. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med. 2016 Aug 25;375(8):730-9. doi: 10.1056/NEJMoa1600159.

Bond AE, Dallapiazza R, Huss D, Warren AL, Sperling S, Gwinn R, Shah BB, Elias WJ. A Randomized, Sham-Controlled Trial of Transcranial Magnetic Resonance-GuidedFocused Ultrasound Thalamotomy Trial for the Treatment of Tremor-Dominant, Idiopathic Parkinson Disease. Neurosurgery. 2016 Aug;63 Suppl 1:154. doi: 10.1227/01.neu.0000489702.18785.5f.

Piper RJ, Hughes MA, Moran CM, Kandasamy J. Focused ultrasound as a non-invasive intervention for neurological disease: a review. Br J Neurosurg. 2016 Jun;30(3):286-93. doi: 10.3109/02688697.2016.1173189. Epub 2016 Apr 22.

Weintraub D, Elias WJ. The emerging role of transcranial magnetic resonance imaging-guided focused ultrasound in functional neurosurgery. Mov Disord. 2016 Apr 8. doi: 10.1002/mds.26599.

Chang WS, Jung HH, Zadicario E, Rachmilevitch I, Tlusty T, Vitek S, Chang JW. Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull. J Neurosurg. 2016 Feb;124(2):411-6. doi: 10.3171/2015.3.JNS142592. Epub 2015 Sep 11.

Gallay MN, Moser D, Rossi F, Pourtehrani P, Magara AE, Kowalski M, Arnold A, Jeanmonod D. Incisionless transcranial MR-guided focused ultrasound in essential tremor: cerebellothalamic tractotomy. J Ther Ultrasound. 2016 Feb 13;4:5. doi: 10.1186/s40349-016-0049-8. eCollection 2016.

Picillo M, Fasano A. Recent advances in Essential Tremor: Surgical treatment. Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S171-5. doi: 10.1016/j.parkreldis.2015.09.012. Epub 2015 Sep 7.

Huss DS, Dallapiazza RF, Shah BB, Harrison MB, Diamond J, Elias WJ. Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy. Mov Disord. 2015 Dec;30(14):1937-43. doi: 10.1002/mds.26455. Epub 2015 Nov 17.

Ahmed H, Field W, Hayes MT, Lopez WO, McDannold N, Mukundan S Jr, Tierney TS. Evolution of Movement Disorders Surgery Leading to Contemporary Focused Ultrasound Therapy for Tremor. Magn Reson Imaging Clin N Am. 2015 Nov;23(4):515-22. doi: 10.1016/j.mric.2015.05.008. Epub 2015 Jul 11.

Fasano A, Deuschl G. Therapeutic advances in tremor. Mov Disord. 2015 Sep 15;30(11):1557-65. doi: 10.1002/mds.26383. Epub 2015 Aug 21.

Ghanouni P, Pauly KB, Elias WJ, Henderson J, Sheehan J, Monteith S, Wintermark M. Transcranial MRI-Guided Focused Ultrasound: A Review of the Technologic and Neurologic Applications. AJR Am J Roentgenol. 2015 Jul;205(1):150-9. doi: 10.2214/AJR.14.13632.

Click here for additional references from PubMed.

Pre- and post-treatment assessment videos courtesy of University of Virginia

     

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