[Automatically generated] From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine, science and clinical practice. Hello, I'm Dr. Christopher Muth, Deputy Editor at JAMA. I'm joined today by Dr. Binit Shah, Associate Professor of Neurology at the University of Virginia and head of the Parkinson Disease and Movement Disorder Division there. Today we will be discussing a JAMA Insights article that Dr. Shah authored along with co-author Dr. W. Jeffrey Elias about essential tremor. Welcome, Dr. Shah. Thanks for having me. So I wanted to start off just talking about when seeing someone with tremor, how do you approach the diagnosis and is there a framework that you use for categorizing or classifying the types of tremor? In evaluating a tremor, we have to keep in mind sort of a couple of factors. One is just our normal medical history, sort of time of onset, time intensity course, exacerbating and alleviating factors, and that can go to a little bit of the differential. But in terms of assessing the tremor itself, probably the most important aspects are understanding what phase of movement the tremor is most prominent with. So a resting tremor predominantly or predominantly a tremor that occurs with some degree of action, whether it's posture or kinesis, target tremor, things like that. There can be some mix in that phenomenology, but really looking at where the tremor is most predominant. And then other tremor features that are important to keep in mind are what's the amplitude of tremor, what's the frequency of tremor, because that also goes into differential diagnosis as well. Okay, great. And now with regard to essential tremor, which was the focus of your article, can you talk a little bit about the classic history and the classic exam findings that one might see in essential tremor? Yeah, and I think an important thing to note is that essential tremor really is sort of a purely clinical diagnosis to make. There are not very many paraclinical tests that can be helpful. And while it's not a diagnosis of exclusion, it is important to ensure that there aren't concurrent factors that could be causing or exacerbating tremor, particularly certain types of medication. Common culprits, including things like amiodarone or beta agonist for reactive airway diseases. Outside of that, the character of essential tremor is one of some degree of amplitude that's more than minimal. So really sort of thinking about two centimeters or greater in terms of rotation around an axis, whether it's a wrist or fingers or even more proximal joints. And then a frequency that's a little bit faster than what we would typically see in, say, a Parkinsonian or a cerebellar tremor. So essential tremor may have a frequency somewhere in the range of 8 to 12 hertz. And the onset tends to be gradual. Many people notice a tremor years before they seek any care or any medical provider notices it, and it can increase with intensity and therefore symptom burden over time. It's not typical for essential tremor to sort of start immediately in a severe fashion, though there are very limited cases of that. But really looking at a slow onset or at least a gradual onset, and demographically, there's not really a specific age group, though there is a little bit of a bimodal distribution of onset in early life, as well as then sort of a tail end of advanced age, increasing likelihood of developing ET. Okay. And then on the exam, essential tremor is going to fall into the category of an action tremor, right, as opposed to a Parkinsonian tremor, which would be more predominant at rest. That's correct. And I think that's an important point to clarify in that, even with rest, people with essential tremor that's severe or even moderate in severity may have some spillover of tremor into the sort of resting state, or they just may not be able to incompletely rest in the office. That doesn't necessarily define the tremor as being resting or Parkinsonian, especially if the tremor clearly gets worse when there's action taken with a limb, for example. And then other things, how about the role of family history? I think that's a really good point. There are a couple of sort of more archaic or less preferred terms for essential tremor, and one of them is sort of a benign tremor. Though if people have quite severe tremor that impacts many of their activities at daily living, I don't think any of us would necessarily characterize that as benign. Another older term is sort of familial tremor, even a combination of benign familial tremor. And it's important to note that ET can run in families, and there are certain very rare monogenetic forms that have been identified. But ultimately, it can very much be a sporadic disorder. So a family history is not required for the diagnosis of essential tremor. And similarly, there can be an exquisite response to alcohol in suppressing tremor. And even that isn't entirely necessary to make a diagnosis, as many patients don't have that alcohol suppression feature. Okay, and you touched on this previously a little bit. But in terms of the differential diagnosis for a tremor that is predominantly with action rather than with rest, what else are you thinking about on the differential diagnosis in terms of other conditions, medications, comorbidities? I think it's always important to trust your general and neurologic exams. If there are features on the neurologic exam that are concerning for deficit that's not just explained by a sort of mono-symptomatic tremor, then further investigation is certainly required. So that could include things like asymmetrical reflexes, weakness, in coordination that can indicate a cerebellar dysfunction. Those would be reasons to consider imaging. In terms of other differential diagnosis considerations, dystonic tremor is rare compared to essential tremor, but is not an infrequent cause of tremor, both at the head or the upper extremities and to the lower extremities to a lesser extent. So there, the tremor with dystonic syndromes tends to be jerkier. There may be an abnormal position or posturing about the joint. And it's fairly accepted that if a tremor starts in the head, then it's generally more accepted to likely be related to dystonic tremor than essential tremor, which may spread to the head later in the course of the involvement of tremor in other parts of the body. Okay. Thanks. That's very helpful in terms of things to think about the diagnosis and refreshing to hear about the focus on the neurological exam and trusting your clinical skills. So now let's transition to talking about treatment for essential tremor. Can you talk about what is the typical first line approach to treatment? Really, the treatment approaches we have are dictated by symptom burden. And so people who have essential tremor may present for evaluation either because they have interference of tremor on their daily or professional or elective activities, or they want to come in for a neurologic assessment to ensure that they don't have Parkinson's disease and PD tremor. And if they don't have signs of bradykinesia, rigidity, or resting tremor that's predominant, we can often reassure them that they don't have Parkinson's, and many people don't require further treatment than that. For people who have truly symptomatic tremor, then our options are sort of broken down into non-pharmacologic treatments, pharmacologic therapy, and then in sort of advanced severe cases, surgical treatments. But first line, I often counsel patients that there can be medications, propranolol or other older beta blockers that have good blood-brain barrier penetration that can suppress tremor both in a scheduled manner or be taken on a PRN basis, as well as the other first line anti-tremor medication, primidone. There are second line agents that can be added both to a first line agent or can be used if there's contraindication or intolerance to one of the first line agents. And the ones that I tend to find most beneficial are topiramate and zonisamide. Though gabapentin certainly falls into that category as do other beta blockers. As far as non-pharmacologic treatments, the value of occupational therapy is probably under-recognized. And many of these patients can often carry on with their needed activities without the need for pharmacologic intervention if they have a good course of occupational therapy. And then going back to the surgical treatments, the two main surgical treatments for patients who have failed more conservative treatment and have a significant burden of symptoms for their tremor include deep brain stimulation and focused ultrasound thalamotomy. Okay, great. That's a really great overview. In terms of the non-pharmacological and the course of occupational therapy, what types of things are done in therapy? So I'll answer as a non-occupational therapist, but from discussing with my colleagues in occupational therapy and patients who have had benefit, for more dexterous tasks, there can be ways of modifying doing those. So it could be an example of trying to write or holding a pen in the traditional way, can exacerbate tremor and can be difficult to do if there's an orthotic device that holds the pen and then patients can then just use more proximal muscle group to control the writing implement. They may be able to write with less dysfunction than if they tried it in the more traditional manner. And in terms of selecting a medication, is there anything that goes into your decision for that? In terms of the first line agents, propranolol is contraindicated in people who have asthma or COPD where there is concern that potentially bronchoconstriction could be unsafe. Outside of that, there are relative contraindications in people with diabetes where symptoms of things like hypoglycemia may be somewhat masked by a beta blocker or in individuals who have uncontrolled depression. Though I would say that many patients tolerate that medication well despite having diabetes or depression. The other thing to be cautious about are patients who may have sick sinus syndrome or bradycardia or tendency for hypotension. In terms of primadone, generally tolerability is the main limitation. There are some issues with certain anticoagulants, including eloquence, where concurrent use of primadone can reduce effective levels of eloquence and so the combination of the two is contraindicated. And when you say tolerability with primadone, what are you referring to? There's an idiosyncratic response of primadone where with the first or first few doses, patients may develop a very severe vertigo. And the exact nature of this isn't well understood, but it resolves generally after a few doses. And it can be mitigated by using a lower dose initially and titrating slowly. Outside of that, primadone can have some sedating effects. And in people who have balance issues, primadone potentially could have a detrimental impact on balance. The article also mentioned botulinum toxin. Can you clarify when that might be considered? That's a really great point. And botulinum toxin, selectively weakening muscle via chemical denervation can really be effective in reducing tremor. Though depending on where we apply it, balancing getting tremor reduction without causing problematic weakness can be a challenge. So in taking the dominant upper extremity, for example, if a patient has difficulty with fine motor tasks, writing, buttoning, or other things like that, we can try suppressing tremor by weakening certain muscles, possibly pronator or supinating muscles. But doing so without causing decrease in grip strength can be a challenge, and it may take many injection cycles to achieve that balance. I'd say from a practical standpoint, one of the main limitations to the use of botulinum toxin is poor payer adoption. Okay. And then moving on to the surgical interventions, presumably this would be considered after a patient did not necessarily have a good response to a trial of medications. And you mentioned the two main types of surgery, either deep brain stimulation or MRI-guided focused ultrasound thalamotomy. So first, can you talk about what are the indications for deep brain stimulation and when you might consider that? I would say that the indications for both surgical treatments are fairly similar in that we are assessing patients who have severe tremor that's disabling, who failed conservative treatment. So it doesn't mean that that conservative treatment hasn't been helpful, but there's still insufficient control of symptoms. And there we look at either deep brain stimulation or MRI-guided focused ultrasound. Deep brain stimulation has been around longer and involves implantation of electrodes on one or bilateral hemispheres of the brain targeting the VIM nucleus of the thalamus. And the exact nature of how it is beneficial is not entirely clear, but we understand from our current understanding of the pathophysiologic mechanism of tremor circuitry indicates that the VIM nucleus of the thalamus is a waypoint for many different tremor pathways. And so the thought with deep brain stimulation is that those electrodes create a high-frequency interfering signal that suppresses the native tremor signals. Okay. And can you talk about what MRI-guided focused ultrasound thalamotomy is and the mechanism by which that acts? Yeah. And even though MRI-guided focused ultrasound is relatively new, the principle that it uses in terms of creating a lesion in the thalamus has been around for decades. Whereas in the past, there was sort of a more open surgery or a burr hole that was necessary to introduce a wire and then thermal heating of that wire via a current of electricity. Now we can use MRI-guided focused ultrasound to increase temperature and create selective ablations where we want to target without the need for an incision in the skull or in the scalp. And it's ultimately a thermal lesion targeting the same nucleus of the thalamus, the VIM nucleus of the thalamus. But rather than overriding abnormal tremor circuits, the focused ultrasound thermally ablates the target so that tremor signals can't propagate. And what's the evidence in terms of the efficacy and also the adverse effects to think about for these different surgical procedures? Generally, we see good benefit with tremor reduction with both surgeries. And it's important to note that both surgeries are done with patients awake. So there's real time assessment, not just of adverse effects at the time of the procedure, but also on the efficacy. And there can be adjustments made prior to the final either implantation or ultrasonic treatment to ensure that we're targeting the most efficacious area. And so it's generally accepted that we get anywhere from a 50 to 80 percent reduction in tremor on the contralateral side of the hemisphere that's being treated. And in terms of adverse effects, there's certainly a slightly different profile between DBS and MRI guided focused ultrasound. Deep brain stimulation requires a burr hole that can be uncomfortable for patients, particularly when they're awake. And there's increased risk of infection simply by virtue of the fact that there's implanted hardware after the procedure is done. The deep brain stimulation also requires a component of the surgery that's under general anesthesia, where there's tunneling of the wire to a pacemaker device or an implanted pulse generator in the chest usually. In terms of MRI guided focused ultrasound, particularly in the clinical trials that we did, we saw transient imbalance and cerebellar ataxia. That usually resolved for most patients within a few hours, but we did see some persistence for a smaller proportion of patients that lasted up to a month and in a few even after that. Additionally, depending on the lesion size, there may be some paresthesia either periorally or on the fingertips in patients who had MRI guided focused ultrasound. And just given the risk of doing lesioning procedures, MRI guided focused ultrasound is indicated to be done bilaterally, but if so, it's done in a staged fashion, whereas deep brain stimulation can be implanted bilaterally at the same initial surgery. Very interesting. And so in terms of thinking about those two procedures, are there certain patient characteristics or other things that might make you think about one versus the other? Generally, patient preference is probably the biggest driver. It's important to note that even though MRI guided focused ultrasound is not incisional, it's a procedure like any other where there is potential risk. And deep brain stimulation and MRI guided focused ultrasound have fairly similar risk profiles in terms of percent of possible complication. That said, both procedures are relatively safe and effective. I'd say if somebody has really problematic tremor bilaterally, particularly in the upper extremities, then deep brain stimulation bilaterally is probably the best initial surgery to consider. If somebody's symptomatology is really more unilateral, then considering either procedure is probably worthwhile. And then in rare instances, we can have patients who, due to other comorbid medical reasons, have higher risk of general anesthesia. And in those cases, we may opt for MRI-guided focused ultrasound, which does not require general anesthesia. Okay. Is there anything else that you want to share about the topic of essential tremor that we haven't already discussed? There are a few experimental therapies that are in various stages of development in terms of pharmacologic treatment for essential tremor. Currently, our pharmacologic treatments are fairly well worn in that they've been around for a long time. And so we may have newer therapies, and what remains to be seen is how they compare in terms of efficacy with the agents we currently have available. But there may be a changing landscape in terms of the treatment from that standpoint. Okay. Very interesting and exciting. And definitely some relevant updates in the past few years. So I'm glad that you were able to write this insights article. Thanks for having me. I'm Christopher Muth and I've been speaking with Dr. Binit Shah about a new JAMA Insights article on essential tremor. You can find a link to the article in this episode's description. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com or search for JAMA Network wherever you get your podcasts. This episode was produced by Daniel Morrow at the JAMA Network. Thanks for listening.