The most common movement disorder, essential tremor often doesn’t respond to meds and depresses quality of life. As neurosurgeon Doris Wang, MD, PhD, explains in this short, information-packed presentation, focused ultrasound can bring immediate and lasting relief to many. She describes the procedure; benefits and potential complications; outcomes data; and how techniques developed at UCSF improve target visualization, enhancing accuracy and effectiveness.
Hello, my name is Doris Wang. I am a functional neurosurgeon and assistant professor in the department of neurological Surgery here at University of California, San Francisco. Today, I'd like to discuss a novel technology, focused ultrasound for the treatment of essential tremor. This is an outline of my talk today. First, I will give an overview of essential tremor, discuss its prevalence, characteristics of the symptoms, as well as main treatment options. Next, I will give an in-depth review of focused ultrasound, what the technology is, how it works, as well as the clinical results. Finally, I will talk about getting focused ultrasound treatment at UCSF, our evaluation process, and the treatment day. Essential tremor is a neurological condition. Characterized by involuntary shaking, usually involving the upper extremities, and the tremors worsen with movement and activity and usually is calm at rest. Essential tremor is the most common movement disorder in the world, affecting 1 to 2% of the population. Its incidence increases with age, affecting about 4 to 5% of the population over the age of 65. The tremors can start at any age with average onset between 40 and 50 years. Tremor can start as early as childhood and follows a bimodal distribution with peak onset in the 2nd and 6th decade of life. In terms of what the tremor looks like, these tremors are characterized by, again, increasing shaking with certain movements and certain with certain actions and with certain postures. It usually involves rhythmic, again, involuntary tremors of the upper extremities, but can actually involve any part of the body, including the head, the voice, or the lower extremities. While essential tremor is a movement disorder, there are other non-motor symptoms that are involved as well. Recent studies have shown that many patients with essential tremor have comorbid non-motor symptoms, including mild cognitive changes, depression, and anxiety. And both the motor and non-motor symptoms of this disease can make activities of daily living very challenging and has a huge negative impact on a patient's quality of life. The pathophysiology of essential tremor is not well known, though it is thought to involve rhythmic oscillations generated by the cerebellum that oscillate throughout the cerebral cortex, the pons, and the thalamus. So the origin of these oscillations is not well known at this point. So when a patient is diagnosed with essential tremor, and the tremors are affecting daily activities, usually the first line of treatment is with medication. There are many types of medication that can be used to treat essential tremor. The most common are propranolol, which is a beta blocker, and primidone, which is an anticonvulsant. Unfortunately, about 30 to 50% of patients may not respond to medical therapy, and plus medical therapy can cause side effects, including slow heart rate, low blood pressure, dizziness, and sedative effects. Another treatment for essential tremor include botulinum toxin injection. And has been shown to be somewhat effective for tremors involving the head and the voice, so Botox injection is not as effective for hand tremor. The other negative side effect of Botox injection included the transient nature of the, uh, therapy, therefore requiring multiple injections to see a long-lasting effect. Surgical intervention has been shown to be a very effective treatment for essential tremor. So brain surgery such as deep brain stimulation surgery or DBS involves implantation of a battery powered device that supplies electricity to leads that are implanted to the brain that can modulate the brain circuits that control movement. It is highly effective, but does require device maintenance, implantation of devices, as well as maintenance post post op. Finally, another type of surgery that can be used to treat essential tremor are ablative surgeries, also known as thalamotomy, where these are non-reversible surgeries that target application of heat to ablate or lesion tissue that drives the ET symptoms. And focused ultrasound is a type of ablative surgery. So focused ultrasound is a type of thalamotomy where we lesion a specific region of the brain. It was approved by the FDA in 2016 to treat essential tremor, and in 2019, focused ultrasound was approved to treat tremor dominant Parkinson's disease. The technology uses up to 1,024 sound waves from a helmet-shaped device that can precisely deliver and safely through the skull with no incisions. These sound waves converge. To raise the temperature inside the brain, and the temperature will raise to such a degree that it can cause permanent lesion of the brain tissue. And the target we're trying to find is the VIM or the ventral intermediate nucleus of the thalamus, which is a target commonly used for deep brain stimulation surgery, as well as other types of surgical thalamotomy. The ventral intermediate nucleus, or the VIM is a very small region in the center of the brain. It measures about 3 by 5 millimeters, and it's located in the thalamus of the brain. As you can see, it's a very tiny region, and identifying it accurately is critical for the success and the safety of the surgery. So this is an animation of how the focused ultrasound works. A patient is placed inside an MRI scanner with this helmet-shaped device around his or her head. Hundreds of ultrasound beams are aimed at the thalamus, part of the brain that's causing the tremor. While each beam is harmless, but just like focusing light with a magnifying glass, where all the beams meet, the temperature rises to the point of destroying that tissue. And this can be done in a very precise way. So thalamotomy has been around for many decades. So what sets focused ultrasound thalamotomy apart from other types of thalamotomy procedures? First of all, focused ultrasound thalamotomy is incisionless. It does not require a craniotomy or burr hole to pass a probe into the target tissue to heat it up. Also, the ultrasound waves can accurately ablate the target tissue with extreme precision. And now with the advent of MRI guided thermography, where we can accurately and in real time monitor the brain tissue temperature as we're performing the procedure. We have a chance to really monitor the amount of tissue or lesioning in real time, ensuring safety and efficacy. Also, we can perform the procedure with a patient awake, where physicians can perform real-time assessment to see tremor improvement and also potential side effects before we commit patient to a permanent lesion. And again, with these 1,024 sound wave sources, we can precisely alter and change the shape of our lesion before we commit to a permanent lesion. So what are the clinical results? These videos demonstrate a patient with a severe central tremor in his right hand before and after the procedure. In the video on the left, you can see that with holding his hands in an extended posture, the right tremor is very disabling and severe. And after his treatment with focused ultrasound, you can see significant improvement in his right hand tremor. So in a landmark study published in New England Journal of Medicine in 2016, 76 patients with moderate to severe essential tremor were randomized to either focus ultrasounds, thalamotomy versus a sham procedure for treatment of their tremor. Primary outcome was tremor rating scale before and after the procedure in between the two patient groups. In the graph here shown on the right, you can see that for those who receive focused ultrasound thalamotomy showing blue here, there's immediate and sustained tremor decrease compared with a sham group. The secondary outcome included significant improvement in disability and quality of life metrics as shown by these bar graphs. Again, those receiving focused ultrasound thalamotomy had significant improvement in disability score compared with those who received sham treatment. So while this study shows significant and immediate benefit of focused ultrasound, are the effects durable? Recently, there have been several articles and studies published on the durability of focused ultrasound thalamotomy in each central tremor. In this one study, which was a perspective study, 4 years after focused ultrasound thalamotomy, there was an average of 56% improvement in hand tremor, 70% improvement in postural tremor, 63% improvement in action tremor, as well as disability compared with baseline. So this and other studies have all shown that there's significant sustained improvement in tremor score over the study period after thalamotomy. As with any surgical intervention, focused ultrasound has its associated adverse effects. Immediately after treatment, the most common adverse events include imbalance, gait disturbances, numbness and tingling in about 1/3 of the study subjects, headache and head pain in about 50% of the study subjects. But of all these adverse events, about half of them resolved within 30 days. An additional but uncommon side effects include dizziness, taste disturbances, slurred speech, fatigue, and vomiting. So out of these side effects, which ones are persistent? So in a study, um, again, from the same group of patients, uh, who underwent the prospectively randomized control trial, after 3 years, persistent, uh, adverse events included imbalance. Unsteadiness, gait disturbances, as well as musculoskeletal weakness and numbness and tingling, but as you can see, all these side effects are very rare. And to summarize, there are many advantages of focused ultrasound thalamotomy. First of all, you see an immediate and durable tremor improvement in the patients. There's significant improvement in quality of life. It is an outpatient procedure where patients can go home the same day. It has little to no risk of infection, there are no implants, probes, or ionizing radiation required for treatment, and oftentimes there's no anesthesia that's needed for the treatment. So now I would like to take this opportunity to talk about focused ultrasound treatment at UCSF and some of the advances that we are doing here. So if you have a patient who's interested in receiving the therapy. The evaluation process consists of evaluation by a neurosurgeon as well as some movement disorder neurologists. So patients should have a confirmed diagnosis of medically refractory essential tremor or tremor dominant Parkinson's disease. They should have failed two first line medications, must be an adult, and can tolerate the procedure by lying still in the MRI for about 2 to 3 hours. Patient should be able to communicate, um, sensations and also improvements during the procedure. That they can activate the stop sonication button if needed to stop the procedure. So contraindications for receiving focused ultrasound include the standard contraindications for obtaining an MRI, including having a non-MRI compatible implant in the body. Also, for patients with skull density ratio of less than 0.5, as calculated from a screening CT is not suitable for the procedure. So during screening, a CT scan is performed to determine the thickness and density of the skull and whether it's suitable for the procedure. During treatment, the patient's hair is shaved to ensure nothing will interfere with the ultrasound waves. Patient's hair will grow back naturally. After local numbing medication is applied, a frame will be secured to the patient's head to ensure there's no movement during the treatment. An elastic cap will be placed to seal the helmet to ensure water will circulate around the patient's head during treatment. During treatment, patient will be laying down in the treatment bed inside the MRI scanner. The medical team will be in the control room. The patient will be able to communicate with the team. The patient's head will be placed in the focused ultrasound helmet, which will be filled with water. And the patient will be given a stop sonication button if at any point the patient needs to stop the treatment. MRI images will be taken to plan the treatment. The physician will first apply light doses of ultrasound energy to identify the correct location in the brain for the treatment, like a test dose. Then full intensity focused ultrasound energy will be applied. The treatment bed will be moved in and out of the MRI machine, and after each treatment, the patient will be tested for clinical improvement in tremor and assessed for any potential side effects. Improvements in tremor should be seen immediately. At the end of the treatment, an MRI scan will be taken to evaluate the size of the lesion. The frame will be removed and the patient will spend an hour in the recovery room and go home the same day. So critical to the success of the focused ultrasound procedure is the ability to accurately identify the VIM region of the thalamus. As I mentioned before, it is a very small region in the middle of the brain. And the VIM also receives cerebellar inputs and it's part of the dentato rubrothalamic tract, the DRT. So identifying the VIM can be challenging sometimes because it cannot be visualized on traditional MRI sequences. On the right image here is the standard T2 weighted image. It's motion degraded and one cannot really visualize where the VIM is located. So most oftentimes, physicians rely on consensus coordinates for targeting with a wake intraoperative testing for confirmation. Here at UCSF we have developed novel ways to visualize a VIM better using MRI technology. So in the right here, you see an MRI image. It's called a proton density scan, which looks for water content within each voxel. And the VIM can be readily visualized these darker areas within the MRI scan. So these images compare a traditional T2 weighted image on the left here and a proton density scan on the right in the same patient, again, showing the region of the VIM using the proton density scan. And as I mentioned before, the VIM receive inputs from the cerebellum, and using tractography, we can map out this fiber tract, the dentato rupothalamic tract, and really lesion at the intersection of the VIM and the fiber tract. This would not only improve accuracy and efficacy of treatment, but can potentially avoid side effects. In conclusion, focused ultrasound is a safe, effective treatment for essential tremor. It uses ultrasound waves to precisely lesion part of the brain that's involved with tremor generation. And here at UCSF we use advanced imaging techniques to improve targeting accuracy and efficacy. If you are interested in pursuing this treatment or have a patient who may be interested, you can email us at bringhaifu@ UCSF.edu. This is also our website for our treatment page for focused ultrasound here at UCSF. And lastly, please feel free to reach out for any questions.
