PADRECC NATIONAL VANTS AUDIO CONFERENCE Diagnosis Pathophysiology and Treatment of Essential Tremor Theresa A. Zesiewicz, MD FAAN March 11, 2010 Thank you everyone. We are going to be talking about essential tremor this afternoon. This will coincide with an update on the American Academy of Neurology Practice Parameter on Essential Tremor, which came out originally in 2005, but is being updated and said to be published we think either this year or early next year. So, let’s get started. So, essential tremor is one of the most common tremor disorders in the world. In fact, one of the most common movement disorders in the world, second probably to ticks. More prevalent than Parkinson’s Disease or Alzheimer’s Disease. It’s characterized by impostural or a kinetic tremor. In the past, essential tremor was considered a benign tremor, but it frequently causes real problems with writing, pouring, eating, every day tasks and activities of daily living and in fact, is not benign. Rather, despite the high prevalence, there’s really only one medication that Food and Drug Administration approved for its treatment and that would be propranol. The good news is that the last decade has certainly witnessed tremendous advances in essential tremor, including the finding that there may be other non-motor symptoms that are associated with essential tremor, possibly including mood and cognitive dysfunction. Additional medications to primidone and propranol, which are medications that are often to treat essential tremor are being identified that may have some inside tremor efficacy, so we are going to go through that today. So, essential tremor is, as we said, more prevalent than Parkinson’s Disease or Alzheimer’s Disease. There’s no world population that’s immune to its development and the age and gender adjusted prevalence of essential tremor is about 3 – 4 per thousand, much more common than Parkinson’s Disease. The incidence of essential tremor rises with increasing age, although essential tremor, unfortunately, can occur in children. About 4% of adults who are over 40 years of age are affected by essential tremor. There is no conclusive evidence that essential tremor increases a patient’s risk for mortality, although, there is one study that founded may be a small increase risk of death in essential tremor patients, but more research is needed to corroborate that finding. So, essential tremor has been thought to have a bimodal age of onset. So, most of you know it to occur either in young patients or in middle-aged patients. There has been a recent study that looks at this and showed that the only time there was a bimodal onset, age of onset for essential tremor was in the Tertiary Care Center and this was possibly because they are young patients who have essential tremor may be more prone to go to an academic institution or a Tertiary Care Center for their care and evaluation of tremor. Let’s look at some clinical characteristics of essential tremor. It is considered to be a heterogeneous condition with variable clinical expression in affected patients. So, it is characterized by a postural and/or kinetic tremor and the frequency of the tremor is 4 – 12 hertz. The frequency will generally decrease over time or the amplitude slowly increases. As most of you know, alcohol transiently diminishes the amplitude by about 50% - 90%, but the problem is once alcohol wears off, the tremor may rebound with a vengeance. The location and amplitude of tremor in the essential tremor patients varies and we don’t know why it varies, why some patients are more prone to a voice tremor, why some patients are more prone to hand tremor and why some have, voice, hands and head tremor. We really don’t understand why this is such a heterogeneous condition. But, we do know that about 90% of patients have a tremor in their hands and arms. About 30% have a head tremor, 20% have voice tremor, 10% have a face or jaw tremor and even 10% of patients have a lower limb tremor, which can sometimes surprise some healthcare providers. You can have an isolated head tremor in as part of the clinical spectrum, as essential tremor, as long as it’s not associated with a dystonia or an involuntary muscle contraction that can be associated with a head tremor as well. About 50% of essential tremor patients have tandem gait abnormalities. So, the recent studies in the past decade have uncovered the presence of non-motor symptoms in essential tremor, Parkinson’s Disease has been found to be associated with non-motor symptoms and these are depression, anxiety, mood, cognitive disorder, those other than the actual tremor. For essential tremor, they also include depression and anxiety, some social phobias and are even some studies by Golanzo that show that essential tremor patients may have more hearing deficits, although more research is needed to corroborate this and more factory dysfunction than age match controls. Now unfortunately, there’s no lab test or radiological scan that aids us in the diagnosis. Essential tremor is a clinical diagnosis and unfortunately also, it’s estimated that about 30% - 50% of cases are misdiagnosed. So, we rely on clinical criteria in the diagnosis of essential tremor. Probably the most widely used statements or consensus statements for the diagnosis of essential tremor was published by the Movement Disorder Society on tremor and this includes the clinical criteria for the diagnosis of essential tremor. The inclusion criteria include bilateral postural tremor with or without a kinetic tremor that involves the hands and forearms that has to be visible and persistent. It has to be a little bit more noticeable. All of us have a physiologic tremor. The duration is greater than five years. The exclusion criteria in this consensus statement include other abnormal neurologic signs. The presence of known causes of an increased physiologic tremor, as well as withdrawal from pharmacologic agents, direct or indirect trauma or a historical or clinical evidence of hypogenic origins for the tremor or a convincing evidence of a very sudden tremor or a stepwise deterioration. So, a patient who has never had a tremor who presents with a very severe or moderate tremor. So, this isn’t on the slide, but I found this recently that Dr. Duschel and Opy proposed the following definitions for three new sub-types for essential tremor. The first sub-type would be hereditary essential tremor. This is for patients who fulfill the consensus criteria that we just went through for definite or classic ET, but also have a family history of it with at least one affected relative with essential tremor. The onset of tremor in the patient and the family member have to be before 65 years of age. The second sub-type is sporadic essential tremor and this is for patients who fulfill the consensus criteria that we just reviewed, but who do not have an immediate family member with essential tremor, but the age of onset of essential tremor is still before age 65. The third sub-type for essential tremor is senile essential tremor and this is for patients who have a definite or classic essential tremor, according to consensus criteria, but who develop essential tremor at or after age 65 years and for senile ET, the patients can either have or not have a family history of essential tremor. So, we will probably be seeing more about the sub-type classifications for essential tremor. Another set of criteria by Elan Louis from Columbia Presbyterian are the Washington Heights-Inwood Genetic Study for Essential Tremor criteria. These include a two parts of moderate postural tremor and in at least one arm. There must be a moderate or two plus kinetic tremor during at least four tasks and the tremors present in the dominant hand or if it is present in the dominate hand that by report, it must have interfered with at least one activity of daily living and we usually ask about eating, drinking, writing, pouring liquids. Now, for those criteria, again we talked about two plus. Two plus would be a tremor of moderate amplitude, one to two centimeter, usually present and it’s clearly absolutory. So, a little bit about the genetics of essential tremor. Essential tremor may be a clearly genetic disease or condition, but not in all patients. About 80% of patients have some genetic components. Probably inherited by autosomal dominant transmission, with incomplete penetrance. But, in some families, the transmission appears to be polygenic. About 50% of patients have an affected first degree relative and a first degree relative of essential tremor patients also appears to be five times more likely to develop essential tremor than a controlled subject. A family history of essential tremor appears to correlate with the younger reporter age of tremor onset. For the pathogenesis of essential tremor, the exact pathogenesis is unknown. The disease may be caused by essential oscillator. This may originate in the gion molorate triangle, that’s located in the brain stem. But, there’s other areas of the brain that have also been implicated in the pathogenesis of essential tremor. These include inferior olevary nucleus and the cerebellum. MODERATOR IS UNINTELLIGBLE has done a lot of work on this and has found the presence of torpedos or external swellings that are identified in the perkinge cells in some essential tremor patients and there’s another study that has found a greater loss of perkinge cells in the cerebellum of essential tremor patients compared to normal controlled. Whether essential tremor is a neurodegenerative disorder of a non-degenerative disorder really remains controversial. Certainly the finding of lewy body pathology or a loss of perkinge cells in some patient’s points toward a neurodegenerative process. But, the condition may be caused by an abnormal oscillatory dysfunction of the motor system and this suggests that it is not primarily a neurodegenerative disease, however, one in which it may be secondary neuronal damage as the disease progresses. What you see here on the slide is that there may be a link between Parkinson’s Disease and essential tremor, but this is very controversial. In a subset of essential tremor patients, we see a rest tremor. This often throws off or confuses healthcare providers. We do get patients with essential tremor who have a mild rest tremor sent to us by general neurologists who feel that it has to be Parkinson’s Disease. There’s no rigidity in those patients often and there’s no Brady kinesia or stiffness and those patients do have essential tremor, but they have a rest tremor sub type. So, the question is, do these patients go on to develop Parkinson’s Disease? Again, this is controversial and more research is needed. Okay, let’s go on to treatment of essential tremor. The first important thing for a healthcare provider is obviously to make a correct diagnosis and also to exclude other possible causes of tremor. This can include co-morbid conditions, hyperthyroidism, withdrawal from alcohol, other phonologic agents, drugs, enhanced physiologic tremor and certainly to differentiate it from Parkinson’s Disease. The other ting is to let your patient know that treatment for essential tremor is not a cure, we are not going to cure the essential tremor, but we offer treatment improvement. Basically for pharmacologic agents, there’s about a 50% improvement in tremor magnitude, but the problem is that there’s 30% - 50% of essential tremor patients that simply do not respond to medical therapy and we don’t really understand why. Some of the medications, some common classes that are used to treat essential tremor include the anti-hypertensive medications. The only medication that the Food and Drug Administration has proved to treat essential tremor is propanolol and this is in the anti-hypertensive class of medications. Propanolol is a non-selective beta anergic receptor antagonist. It does effectively treat tremor. It receives a level A recommendation in the American Academy of Neurology Practice Parameter. It also comes in a long acting preparation. Other anti-hypertensive medications that have been discussed or have been studied rather, to treat essential tremor include atenolol or tenormin and sotalol or sotacor. They actually have been studied and have received a level B level of recommendation from the American Academy of Neurology. Others including nadolol or corgard or nimodipine or nimotop, may treat essential tremor with a lower level of recommendation. Medications like verapamil or calan or nycetapine or avalide have not been shown to effectively reduce tremor. There are studies of other anti-hypertensives and these include clonidine, catapres, flamazine, metosol or ??, nicardipine or cardene, the research on these is either limited or they have produced conflicting results. So, the potential use in treating tremor is really uncertain. The next common class of medications to improve tremor are the antiepiletics and the second agent that has received a level A recommendation in treating essential tremor is primidone or mysoline. Mysoline is an antiepiletic drug that effectively treats essential tremor. Many studies over the past 20 years have examined the use of primidone or mysoline in treating tremor and have demonstrated about a 50% reduction in tremor magnitude and they can give a first line agent in treating essential tremor. The problem with primidone or the frequent side effects, particularly in the initial stages titration and the side effects can include anything from nauseau, dizziness, sedation, horrible flu like symptoms, vertigo, even a lower initial dose and a slower titration has not been shown to effectively reduce the adverse result of the events. We normally start with a half of a 50 mg tablet once a day and increase every week by half tablets until some effect is reached. Topiramate is an antiepiletic that actually has been studied very large randomized multisensored, double blind trial and topiramate was found to effectively treat essential tremor by about 29% as rated on the Fahn-Tolosa-Marin Tremor Rating Scale compared to a 16% improvement in placebo treated patients. The average mean dose in this study was about 292 mg a day, although, there was a between a group difference significant at 62 mg a day, so I don’t think its necessary to go up to 292 mg a day, I think we can go up to 62, roughly 75 mg and we should see some significant benefit in essential tremor. Again, the problem with topiramate are the side effects. There was a great than a 30% drop out in the study. The side effects of topiramate include parastesias, weight loss, taste abnormalities, memory difficulty, appetite suppression, two additional ones are kidney stones and also if a patient has an allergy to sulfur drugs, care is warranted in treating a patient with topiramate. Another antiepiletic medication is galatentin, neurontin. Neurontin was shown to treat essential tremor in a small number of trials. It was found to be effective as mono therapy, but was not found to be effective as adjunct therapy. Zonisamide or Zonegram is an anticonvulsant that has some anti-tremor efficacy, but the study results are mixed. We actually did a study on zonegram, the original studies came from Japan and the authors compared zonisamide to arotinolol, which is an anti-hypertensive agent and found that zonisamide was effective in treating essential tremor. In our study, we did find significant anti-tremor efficacy from zonegram, but we had a greater than 30% drop out rate and again, due to side effects, such as fatigue, diarrhea and headache and none of the patients opted to stay on zonegram for tremor. Levetiracetam or keppra medication is an antiepileptic that has strong specific finding to cerebellum receptors. Several studies failed to show significant tremor reduction with the use of keppra, although there is one study by MODERATOR IS UNINTELLIGBLE, that showed a acute reduction in tremor, minutes after taking keppra, but in the studies where patients were treated with keppra for several weeks, chronically, there was no difference between patients who were treated with keppra and those patients who were on placebo when it came to reducing tremor. Pregabalin or lyrica, there effective essential tremor is unclear. There are two controlled studies with opposite findings. We had one that showed that pregabalin actually by tremoromotry significantly reduced the amplitude of essential tremor in 20 patients. Jojankovic and Dr. Solora had a study on 20 essential tremor patients that failed to find any significant improvement in the Fahn-Tolosa-Marin Rating Scale. I guess the difference there is that their study used a rating scale and we used a tremoromotry device. So, there is an ongoing study currently on 62 patients and pregabalin or lyrica on essential tremor that is currently running. So, in the quest to find other medications that reduce tremor, there are lots of different medications that have been tried. Antibiotics, for example, none of them have really shown to be beneficial, isoniazid, an anti-tuberculosis medication was evaluated in a trial, but was not terribly successful. Some of the anti-depressants have also been used to treat essential tremor, but without success, mirtazapine or remeron or trazodone or desyrel, there are case reports that indicate that they have had some anti-tremor efficacy, but they have not been shown to have this in controlled trials overall. There are some anti-psychotics that seem to have anti-tremor efficacy. For example, clozapine, which is an A typical neuroleptic. It has minimal extraparametal side effects. It has been shown to reduce tremor by quite a lot, about 45% - 50% in two controlled studies. The problem with it is that is has a very serious possible side effect. It has a 1% risk of a granulo psychosis. So, its use is only reserved for very refractory cases of tremor. The white cell counts need to be taken and ziprexa or lansapine also have possibly some benefit in reducing tremor, but again, some serious side effects in terms of extrapyramidal events. The antivirals, amantadine or symmetrel an antiviral medication that’s used to treat Parkinson’s Disease. One open label study evaluated it and found that there was really no difference in patients who received amantadine compared to those who were put on placebo. So, because primidone or mysoline is metabolized to a barbiturate and it as anti-tremor efficacy, there are other studies that look at barbiturates, specifically, Phenobarbital and interestingly, two double-blind studies looked at Phenobarbital and failed to find that Phenobarbital on its own decreased essential tremor compared to patients who took placebo. Now, the benzodiazepines are a little bit different, alprazolam or xanax has been shown to reduce or treat clinical ratings or improve clinical rating scales of essential tremor in two double –blind placebo controlled trials. However, it needs to be as cautiously because of its high potential for abuse. Conversely, clonazepam or klonopin has mixed results. One study showed that there was an improvement in tremor efficacy, while the other study did not, so it was not recommended or received a high rating for its use. Bronchodilators, this is very interesting because I think that everyone knows that bronchodilators can actually worsen tremor, but there are several tremors that looked theophylline, xanthine derivative in the bronchodilator on essential tremor, at least one study showed quite significant improvement in treating tremor, but another study showed exact opposite and these are conflicting results, so it was not recommended for use. The carbonic anhydrase inhibitors, there was controlled studies of two carbonic anhydrase inhibitors, acetazolamide or diamox or methazolamide or neptazane and although when I was a fellow, we were used to use some of these off label in some patients. The controlled trials really have failed to find a significant difference in tremor evaluations in patients who are treated with these medications compared to placebo. So, the treatment consideration for pharmacologic agents are that both primidone and propanolol, one is an antihypertensive and one is an antiepileptic, have substantial evidence that support their effect in reducing symptoms of essential tremor. The problem is greater than 30% of patients will not respond to either of these agents. You will see about a 50% improvement in magnitude of effect as initial therapy, the choice as to which one to use depends on the co-morbid symptoms or conditions of the patient, such as asthma, for example, you should not use a beta blocker and primidone can be very difficult to use particularly in the beginning and early stages of titration. Both of these medications have shown tremor efficacy for at least one year. There are some evidence for reduction and tremor control over time and you may need to dose increase both medications. Patients ask us about botulinum toxin. In refractory cases, I do use botulinum toxin to treat essential tremor, although there is a significant side effect from it and that is hand weakness. There is one randomized trial that used a low dose and higher dose of botulinum toxin on limb tremor in 133 patients over a four-month period. There was significant improvement in tremor, but the problem that hand weakness occurred in 30% of patients who received 50 units of botox and 70% of patients who received 100 units of botulinum toxin. If the patient has an essential tremor or tremor in the dominant hands and they need to operate a car or other machinery, even activities of daily living, they are unhappy with this. The tremor decreases, but there’s quite a cost to this. Surgical treatment does provide treatments for refractory tremor. In the 90’s this began as thalamotomy, which was a stereo tactic procedure that created a lesion in the ventral intermediate nuclear of the thalamus and studies typically reported an 80% - 90% improvement in tremor symptoms compared to base line. There were significant side effects with thalamotomy, however, and that included MODERATOR IS UNINTELLIGBLE, some cognitive deficits, weakness, confusion, even stroke in some cases and there was a very wide range of side effects with thalamotomy, if you look at these studies, 14% - 47%, most of the side effects resolved over time, but for example, in one study, hemiparesis and speech difficulty persisted in about 16% of cases. So, due to the risk of these adverse events, bilateral thalamotomy is no longer performed to treat essential tremor, but using placement strategies of thalamotomy, deep brain stimulation uses the high frequency electrical stimulation from an implanted electrode to modify the activity of the target area. In this case, the ventral intermediate nucleus of the thalamus. The electrodes are connected to the pulse generator and that’s implanted in the chest wall. DBS is very effective in treating essential tremor, the improvement is about 60% - 90% on the clinical rating scales over time. The adverse events have been reported in about 18% of patients in various studies and these events are usually related to equipment malfunction, lead placement. There can be more serious side effects, such as dysarthrea, imbalance, weakness, even stroke and seizure. So, surgical treatments of essential tremor is generally reserved for patients who are refractory to pharmacal therapy. Thalamotomy and deep brain stimulation, both suppress tremor and again, the choice of procedure depends on the patients circumstance, risk of complications, we really at movement disorder centers, almost completely use deep brain stimulation at this time. It’s reversible, a reversible procedure and the side effect profile just seems to be a little bit more palatable than the unilateral thalamotomy. So, despite being one of the most prevalent movement disorders in adults, obviously, there are still lots of gaps in the knowledge and pathogenesis of essential tremor, although there have been great strides made. Again, 50% of patients may be misdiagnosed, 30% - 50% will not respond to treatment and it is important to realize that there are symptoms of essential tremor that can overlap with those of Parkinson’s Disease. It is very important for physicians to understand the disorder and the diagnosis. There are two medications that have level A recommendations in treating it. Those being primidone and propanolol. The level B recommendation medications include atenolol, sotalol and xanax, as well as toparamate. There are some level C recommendations, botulinum toxin, may help in refractory tremor and in refractory essential tremor, but unfortunately, its use is dose dependent for hand weakness. Surgical treatment is very useful and efficacious in treating essential tremor with a deep brain stimulator, again, it is used for refractory tremor for those patients who have failed pharmacol therapy. Okay, I think we are a little bit ahead of schedule. I did want to point out, maybe you want to talk about this. I did put this document on the live meeting site that kind of summarizes and this is also available to download if people want to look over here where there’s the little three pages that says hand out. So, if you want to talk about this for a minute and then I will call in and open the lines so people can ask questions. So, MODERATOR IS UNINTELLIGBLE, on essential tremor, the American Academy of Neurology decided in 2000 produce an evidence based guideline for healthcare providers in treating essential tremor. It took five years and it finally was published in 2005. I think we looked at thousands and thousands of articles. We were struck at the heriginaty of a lot of the research that was available, but after we put everything together, you can see that primidone and propanolol, as we as proponolol long acting received a level A recommendation for treatment for essential tremor. Level B recommendations mean that they are probably effective for xanax, atenolol, gevapentine as mono therapy, sotalol and toparamate, but I will caution that a level B recommendation, doesn’t necessarily mean that the medication isn’t as good as a level A. In some cases, it means that the research is not available for the medication to receive a level A recommendation. So, a level A means that a pharmacologic agent has to have two very convincing, double-blind placebo trials, showing that it is efficacious. If a medication has greater than a 20% drop out rate, such as in the case of toperamate, which had about 30% - 32% drop out rate, the level of evidence is downgraded. So, it received a level B level of recommendation. Level C are those medications or treatments that are possibly effective. This include klonopin or clonazepam. Clozapine, again used with caution. Nadolol and nimodipine and also botulinum toxin for refractory cases because of the possible weakness. For the update in essential tremor, which will be coming out either this year or early next year, we have lots of levels used, including pregabalin, some of the other medications. Nothing major different though when I look at some of these medications. There is some evidence that suggests that some treatments are ineffective in treating tremor. Trazodone was one of them, MODERATOR IS UNINTELLIGBLE, and level C recommendation again with MODERATOR IS UNINTELLIGBLE, and then the insufficient evidence group is huge. Why gavapentine has not been shown to be efficacious as adjunct therapy, but has been shown to be efficacious in mono therapy is just not proved and you will see some others there, MODERATOR IS UNINTELLIGBLE. What you don’t see on this summary of the guideline is that there was some evidence that common use of primidone and propanolol was more efficacious than using either agent alone. So, although we almost never do it, sometimes there seems to be a little bit of an additive effect. Evidence, I have used lyrica with primidone, for example. So, I think there has to be more research to look at some of the possible additive effects of lower doses of some of these medications in treating essential tremor. There’s something here about pharmacological treatment for head tremor. Propanolol is probably effective in treating head tremor and botulinum toxin was possibly effective in treating head tremor. There really needs to be more research regarding voice tremor. There were two small studies that showed botulinum toxin was possibly effective voice tremor associated with ET, but again, the side effects botulinum toxin were the breathiness of the voice that occurred in a large number of patients and that persisted for several weeks and was very bothersome to patients. Okay, if you all stand by, we will get the lines open. Please hold. Okay, the lines are open. If there are any questions out there, please introduce yourself and say where you are from and ask your question. We have a quiet audience out there today. Or there are no questions. Exactly. You were so thorough. It really makes me think, gosh we have to find some more medicine, don’t’ we? I agree. It’s really frustrating for the patients. I think that I have been sending more patients for surgery. My patients level is decreasing and I think that the surgeons are much more well versed. Deep brain stimulation now, how long has been out, about 17 years? A long time. I remember the first one and it was just miraculous. When you blind-folded the patient and they would hold a glass of water and then they would turn it on and turn it off and you just couldn’t believe, it was just so efficacious in treating patients. But things do go on and it still has to be used with caution. Right. But we need more for people in the middle that aren’t severe enough. Yeah, we need more research. That use the DBS. Right. Well folks, are there any other comments or questions out there? WE don’t have a problem with ending the call early, but you are certainly willing to entertain any comments or questions. I would just like to thank Dr. Zesiewicz for a very nice job. Thank you. END OF CONFERENCE. PADRECC National Vants Audio Conference Diagnosis Pathophysiology and Treatment of Essential Tremor Theresa A. Zesiewicz, MD FAAN March 11, 2010 Page 1