The AAN has released an updated evidence-based guideline on the treatment of essential tremor (ET), one of the most common movement disorders, in the Oct. 19 online edition of Neurology. The guideline was based on a review of the scientific literature from 2004 through April 2010, as well as the studies considered for a previous guideline, released in 2005.
Theresa Zesiewicz, MD, AAN Fellow — professor of neurology at University of South Florida (USF) in Tampa, director of the USF Ataxia Research Center, and director of the Frances J. Zesiewicz Center and Foundation for Parkinson's Disease at USF — who chaired the AAN Quality Standards Subcommittee that completed this review, spoke to Neurology Today about some of their most significant findings. Here, she explains why the updated guidelines are important for both clinicians and patients, as well as why research may have lagged in recent years and needs to be reinvigorated.
WHAT ARE THE MOST IMPORTANT FINDINGS FOR TREATMENT FROM THIS REVIEW?
Blood pressure medications and antiseizure medications continue to be in the lead in terms of therapy for ET. Atenolol and sotalol are beta-blockers; they are also used for blood pressure, and they have a Level B recommendation for use.
Also importantly, the guideline did reiterate that propranolol and primidone continue to be effective agents in terms of effectively treating ET, with Level A recommendations.
One of the things that's very interesting is that surgery has a very high magnitude of effect in treating tremor — especially deep brain stimulation (DBS) to the ventral intermediate nucleus of the thalamus. Unfortunately in these guidelines, because sham surgery is controversial and usually not done, DBS received a Level C recommendation. However, in patients who are refractory to medical therapy for tremor, surgery certainly can be an option and appears to be extremely helpful — with a higher magnitude of effect than medication use.
So, one of the most important things to understand from these guidelines is that just because therapy has a Level C recommendation doesn't mean that it's necessarily a third-line therapy. What it means is that we only have a Level C recommendation because that's the grade of research evidence available.
The other very important thing is that more research is needed because such a high percentage of ET patients don't respond well to medical management.
WHAT IS NEW IN THIS UPDATED GUIDELINE?
We found that some medications probably do not reduce limb tremor. One of them is levetiracetam (Keppra), and another one is 3,4-diaminopyridine; they both received Level B recommendations against their use. A medication that has been studied as tremor therapy, especially overseas, is flunarizine, but it did not seem to improve ET and it can lead to the side effect of parkinsonism, so it received a Level C recommendation against use.
There was either inconclusive evidence or conflicting evidence regarding the following medications: pregabalin (Lyrica), zonisamide (Zonegran), and clozapine (Clozaril). These all got a Level U recommendation.
Topiramate continued to receive a Level B recommendation in favor of use in ET. We reviewed a more current, large study on topiramate, but we continued to give it a level B recommendation because of the relatively high dropout rate. In addition, olanzapine (Zyprexa) continued to receive a Level U recommendation. A 2005 study comparing olanzapine with propranolol yielded only Class III evidence.
WHY DID YOU CONDUCT ANOTHER REVIEW JUST SIX YEARS AFTER THE FIRST GUIDELINES WERE RELEASED?
Well, the first guideline was done in 2005, so we wanted to determine whether any new medications or new research was available to help patients with ET. Approximately 30 to 50 percent of patients who are on these [current] medications don't really get benefit from them, and, unfortunately, over time, it appears that there is at least a subgroup of patients in whom the medical therapy will not continue to work after years and years and years. We're always looking for new medications, and it's important to put them through a rigorous process like this to see if we can come up with better recommendations for patients.
WHAT DO YOU THINK THE AREAS OF RESEARCH NEED TO BE RIGHT NOW?
We need to have more pilot trials — especially small crossover studies — in medications to see if we have a signal as to whether these medications will have some benefit. These may determine whether larger clinical trials will be undertaken. And I think that we have to continue looking at other preclinical research as well, which may provide pathophysiology.
Many researchers think that ET is actually a conglomerate of diseases rather than just one disease. There's a lot of heterogeneity to ET. And as we learn more about the pathophysiology of ET, I think we're going to be able to find new and better therapies and new mechanisms of action to treat it.
WHY ARE EFFECTIVE MEDICATIONS SO DIFFICULT TO IDENTIFY FOR ESSENTIAL TREMOR?
Years ago, when essential tremor was called benign essential tremor, I think we lost ground because there was the notion that this was an innocuous condition — and it's not. There are actually possibly nonmotor symptoms that are associated with ET, and this is a progressive disease. And it is a disease, not just a benign condition.
The research that occurred with primidone and propranolol occurred in the 1980s, and approximately 30 years later, they are still the Level A–recommended medications.
I would hope that a parameter like this would point out that more research is needed and that we need to make a more concerted global effort towards better treatment. But I try to give a positive message to the patients that we can treat many ET patients — I don't want patients to be discouraged.
When I talk to ET patients, they tell me that sometimes they feel that they are not taken seriously by their doctors, who just feel that they just have a “tremor.” This needs to change.
IS THERE ANY PREINDICATION AS TO WHETHER A PATIENT WITH ET WILL RESPOND TO MEDICATION? TREMOR TENDS TO WORSEN WITH AGE; DOES THAT HAVE AN IMPACT ON THE EFFECTIVENESS?
There is no indication as to whether a patient will respond or not. And the other problem is that there are significant side effects to some of these medications. Propranolol can lead to depression and erectile dysfunction. Primidone, while it is very effective in treating ET in a group of patients, can cause very debilitating side effects — such as ataxia, visual disturbances, nystagmus, headache, and dizziness —especially as it's being titrated up. So we really don't know which patients are going to be able to handle it or not.
The choice of medication for the patient really depends on the comorbid conditions. You wouldn't want to try to use propranolol in a patient who suffers from depression, for example. Topiramate, which has a Level B recommendation, can result in kidney stones.
HOW CAN NEUROLOGISTS USE THESE GUIDELINES IN THEIR PRACTICE?
I think the important thing is to first make an accurate diagnosis. Once this is done, the choice of which meds to use can depend on concurrent comorbidities. However, the level of research evidence can assist healthcare providers in making a good choice for treatment. Propranolol and primidone still have Level A recommendations. However, other options are available and are present in the guideline. We also indicated which medications will not treat ET.
I think they [the guidelines] are helpful, and I think that it's good every 5–10 years to re-review the literature. Hopefully we'll find a path forward.