Experts Review Surgical Treatments for Essential Tremor

We are fortunate that ET experts recently reviewed surgical treatments for ET to write this paper entitled Surgical Treatments for Essential Tremor. They include DBS (deep brain stimulation), FUS (focused ultrasound surgery/ablation), SRS (stereotactic radiosurgery), and radiofrequency ablation treatment. The authors detail when surgical treatment is an option (when tremor symptoms are severe) plus they cover complications and outcomes, including limited effectiveness and possible need for repeat or additional surgery. Details are also included for those with voice and head tremor. Patients may have tremors bilaterally, that is on both sides of their body, however certain surgeries are found to have better outcomes if the procedure is done unilaterally, meaning the outcome affects only one side and is therefore a partial solution.

For a better understanding of what is happening in the brain of someone with ET, read the paper’s introduction. It explains how the tremor signals travel along a communication loop in the brain known as the corticobulbocerebellothalamocortical loop. It also tells how the surgeries for ET target the ventralis intermedius (Vim) or the posterior subthalamic area (PSA) right below the Vim, and surgical stimulation in these spots disrupts the signals in the loop, lessening tremor.  If we can locate a visual image of this loop we will post it! The authors’ key issues, conclusions and expert commentary are worth reading especially for those interested in surgical options with supporting data. Overall, the authors, Elble, Shih and Cozzens comment on the rapid improvements being made in surgical treatments.

This paper was supported in part by a grant from the Illinois-Eastern Iowa District Kiwanis Neuroscience Foundation.

Surgical treatments for essential tremor

Maryland Essential Tremor Support Group Welcomed Dr. Paul Fishman to Meeting

 The Columbia, Maryland ET support group was pleased to welcome Dr. Paul Fishman on 2/3/17 as a guest speaker for the monthly meeting at The Wellness Center. Dr. Fishman performs both Deep Brain Stimulation (DBS) surgery and the newer MR-guided Focused Ultrasound Surgery (FUS) on ET patients.

We were fortunate to have him visit and share his informative presentation with us.

Click here for presentation notes.

Present-Day Essential Tremor Medical Research Outlined:

Experts Reach Consensus on Research Priorities

In the quest to advance Essential Tremor (ET) research that could lead to better understanding and development of successful treatments, medical professionals in the movement disorder field collaborated on a white paper published in December, 2016 entitled “Knowledge Gaps and Research Recommendations for Essential Tremor.”

ET_poster (1)The paper developed out of a workshop these professionals attended in May 2015 and their subsequent brainstorming discussions. The non-profit ET patient advocacy organization HopeNET, which has for several years sought to connect the ET patient community to the medical research community, proudly played a role in the occurrence of the workshop, which was hosted by the National Institutes of Neurological Disease and Stroke (NINDS) in Bethesda, Maryland, USA, and included over 60 participants.

The resulting paper is a valuable guideline for the future. It is certain to be of interest to the ET community who will be glad to learn that medical professionals are indeed working to further knowledge of this movement disorder! The summary below serves as a layperson’s general overview of the detailed paper to convey information in terms that are more understandable to a general audience. Science-curious readers can pursue the paper in full through ScienceDirect here [1].

The causes of ET are poorly understood. Despite widespread occurrence, no medications have been created specifically to treat it. The goals of making ET less elusive and coordinating research efforts were driving forces behind the workshop discussions. One big challenge is limited knowledge about both the genetics and the neural pathway mechanisms involved in ET. Another has to do with inconsistencies in making an ET diagnosis. The fact that ET has multiple causes makes any simple definition of it inadequate.

Clinical research methods and approaches have been inconsistent. And without standardized procedures in place, analyses and findings disagree. The authors do an excellent job of taking an in-depth look at what they do and do not know about ET. Perhaps most importantly they take it a step further: they come to a consensus on recommendations for research in these areas: phenomenology and phenotypes, therapies/ clinical trials, physiology, pathology and genetics.

The authors recall the classic ET definition given roughly 20 years ago, as set forth by the International Parkinson and Movement Disorder Society (MDS). They mention that since that time there has been speculation about other characteristics that may need to be added to the definition such as, modest changes or abnormalities in these areas: cerebellar [2], cognitive [3] and hearing function [4, 5], plus dystonia [6].

The authors discuss how it is common for ET patients to present with new symptoms that do not fit in to the existing ET definition, changes that call into question the validity of the diagnosis. ET also appears to share overlapping features with other conditions [7]. New symptoms and overlapping features have encumbered clinicians, but they still believe a revised, workable definition is necessary clinically for the purpose of making inroads and facilitating important collaborative research.

They agree on new criteria and propose that ET going forward be considered as an isolated tremor “syndrome” rather than a single disease or condition since it has been established that ET has multiple causes.

The following are the authors’ recommended diagnostic criteria for defining ET as an “isolated tremor syndrome” in an individual:

  • Bi-brachial action tremor (postural or kinetic)
  • Duration of 3 years or more
  • With or without head tremor or tremor in other locations
  • No other diagnostic neurologic signs (e.g. overt dystonia or parkinsonism)
  • No identifiable endogenous (e.g., autoimmune disease) or exogenous (e.g., toxins) disturbances that could cause tremor
  • Difficulty with tandem walking is permissible, but no abnormality of gait [8]

Bi-brachial pertains to the 2 arms. Postural refers to holding a limb against gravity as in for example, holding arms out in front of the body, and kinetic refers to tremor that occurs when in action. The authors acknowledge that there are isolated tremors that do not meet the proposed ET criteria. They make clear this clinical ET definition is not meant as a detriment to continued research on other isolated tremors.

Given the absence of an identified ET gene or an identified biomarker to help with a diagnosis, emphasis is placed by the authors on gathering and classifying symptoms as fully as possible, with quality data collection and standardization efforts in place, including use of common data elements (CDEs). How is tremor measured in a clinical setting? Various tremor rating scales are used and the authors are calling for their evaluation. The rating scales include clinical assessment scales, patient-reported ratings/scales, and motion transducers, which are those devices that measure tremor amplitude or severity. Recommendations are made for development of a tremor monitor, among other technological devices. It is however pointed out that gaining insight from measuring the tremor is not as conclusive as it would seem since tremor amplitude or the severity of the oscillation can fluctuate at various times and the significance of those fluctuations is not known.

Regarding therapies or treatments for ET, the common drugs presently used were created to treat other conditions like epilepsy, high blood pressure and anxiety and were repurposed for ET when found to reduce tremor in some people. The paper explains briefly how these agents are thought to work at the cellular level. Besides the commonly used beta-blockers, anti-epilepsy drugs and benzodiazepines, clinical research has established ethanol, aka alcohol, as effective in its ability to reduce tremor amplitude for many people. Its effectiveness has led to studies in past years that isolate ethanol-related molecules such as sodium oxybate, 1-Octanol and octanoic acid, and these may turn into possible future treatments. They also seek to better understand how certain surgical interventions have met some success in reducing tremor: deep brain stimulation (DBS) and magnetic resonance focused ultrasound, both of which target and lesion the ventral intermediate nucleus (VIM) portion of the thalamus in the brain.

At the physiological level, researchers have identified a particular central nervous system circuit they think may be responsible for tremor oscillation in ET called the corticobulbocerebellothalamocortical circuit, and they are calling for investigation of it.

Genetics research findings make clear to the authors that the path to increased ET knowledge may be found in focusing on large patient cohort studies worldwide in order to make certain associations. Background is given on some important studies that have been done such as the Icelandic genome-wide association study (GWAS) that suggests the gene LINGO1 has possible associations to ET [9]. Common data elements, collection and storage of DNA bio-samples and coordinated multinational efforts are strongly encouraged.

The paper builds an awareness of scientific research being done in the ET field. The workshop provided an opportunity for experts to discuss present-day ET challenges. The authors discovered shared goals that ultimately revolve around deepening knowledge and making new treatments available, improving data, standardizing approaches, and evaluating therapies. It is a guideline for future research projects that, if adopted by researchers, could see momentum build in the direction of better outcomes for ET.

Lisa Gannon

 

 

 

References:

[1] F. Hopfner, D. Haubenberger, W.R. Galpern, K. Gwinn, A. Van’t Veer, S. White, …, G. Deuschl. Knowledge gaps and research recommendations for essential tremor. Parkinsonism and Related Disorders 33 (2016) 27-35. Retrieved from http://www.sciencedirect.com/science/article/pii/S1353802016303893

[2] J. Benito-Leon, A. Labiano-Fontcuberta, Linking essential tremor to the cerebellum: clinical evidence, Cerebellum 15(3)(2016) 253-262.

[3] E.D. Louis, J. Benito-Leon, S. Vega-Quiroga, F. Bermejo-Pareja, Neurological Disorders in Central Spain Study, Faster rate of cognitive decline in essential tremor cases than controls: a prospective study, Eur. J. Neurol. 17(10)(2010) 1291-1297]

[4, 5] W. G. Ondo, L. Sutton, K. Dat Vuong, D. Lai, J. Jankovic, Hearing impairment in essential tremor, Neurology 61 (8)(2003) 1093-1097.

Benito-Leon, E.D. Louis, F. Bermejo-Parmejo-Pareja, Neurological Disorders in Central Spain Study, Reported hearing impairment in essential tremor: a population based case-control study, Neuroepidemiology 29(3—4)(2007) 213-217.

[6] J. Jankovic. Essential tremor: a heterogenous disorder, Mov. Disord. 17(4)(2002) 638-644.

[7] R.J. Elble, What is essential tremor? Curr. Neurol. Neurosci. Rep. 13(6)(2013) 353.

[8] F. Hopfner, et al. Knowledge gaps and research recommendations for essential tremor. Parkinsonism and Related Disorders 33 (2016) 27-35, http://dx.doi.org/10.1016/j.parkreldis.2016.10.002

[9] H. Stefansson, S. Steinberg, H. Petursson, O. Gustafsson, I.H. Gudjonsdottir, G.A. Jonsdottir, …, K. Stefansson. Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat. Genet. 41 (3)(2009) 277–279.

Analysis of Visual-Motor Task Electrophysiological Activity During Deep Brain Stimulation for Treatment-Resistant Movement Disorders Study

INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH) and Suburban Hospital.

First, we want you to know that:

Taking part in NIH research is entirely voluntary.

You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking part in a study or be under evaluation for study participation.

You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.

Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH doctors or research team before you agree to the study.

Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other health professional.

Purpose of This Study
The aim of this study is to better understand activity in particular areas of the brain that might be involved in Parkinson’s disease and Essential tremor, and how the activity may change after deep brain stimulation (DBS) surgery in these disorders.

Facts That Led us to This Study
Previous research has shown what areas of the brain might be involved in symptoms of Parkinson’s disease and Essential tremor. This research has led to the use of DBS to treat these conditions. Some of the brain areas that might not function properly in people with these disorders are also involved in making decisions. To learn more about these brain areas, we will use a test that involves decision making to study brain cell activity before, during and after DBS surgery for these conditions. We will look at brain activity before and after surgery using a technique called magnetoencephalography (MEG). We will look at brain activity during surgery by recording directly from the surface of the brain.

Study Population
6 people with Parkinson’s disease, and 6 people with Essential tremor will participate in this study.

Inclusion Criteria
To be eligible to participate in this study, you must:

  1. Be at least 18 years old and have been diagnosed with Parkinson’s disease or Essential tremor.
  2. Be scheduled to have DBS for your condition.

Exclusion Criteria
You may not be eligible for this study if you:

  1. Have untreated depression or another psychiatric disorder
  2. Use illegal drugs
  3. Are pregnant
  4. Are uncomfortable in small, closed spaces (are claustrophobic)
  5. Have any metal in your body that would make having an MRI scan unsafe or would interfere with the MRI scan such as: cardiac pacemaker; implanted cardiac defibrillator; aneurysm clip; neuro or bone stimulator; insulin or infusion pump; implanted drug infusion device; cochlear, otologic, or ear implant; prostate radiation seeds; IUD (intrauterine device); transdermal nitroglycerin patch; any type of prosthesis (eye, penile); heart valve prosthesis; shunt (spinal/intraventricular); wire sutures or surgical staples; bone/joint pin, screw, nail, plate; body tattoos or makeup (eyeliner/lip); body piercing that cannot be removed; breast tissue expander; or other metal

Procedures
Study overview:

This study requires 5 study sessions over several months. The first 2 sessions will be in the NIH outpatient clinic before your surgery. The 3rd session will be during your surgery at Suburban Hospital. The 4th and 5th sessions will be at NIH, 3 and 6 months after your surgery.

Study session #1:
During the first study visit, we will ask you about your medical history and perform a neurological examination. Women who are able to get pregnant will have a pregnancy test. You will not be able to participate if you are pregnant. You will also have an MRI scan of your brain. This visit will last about 3 hours.

MRI uses a strong magnetic field and radio waves to take pictures of your brain. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. During the MRI scan, you will lie on a table that can slide in and out of the cylinder. You will be in the scanner about 20 minutes. While in the scanner you will hear loud knocking noises and you will be fitted with earplugs or earmuffs to muffle the sound. You can communicate with the MRI staff at all times during your scan, and you may ask to be moved out of the machine at anytime.

Study sessions #2, #4 and #5:
Study session #2 will be no more than 6 weeks before your surgery. Study session #4 will be 3 months after your surgery, and session #5 will be 6 months after surgery. During each of these visits we will conduct neuropsychological testing that will include standard assessment scales. We will record the activity of your brain using magnetoencephalography (MEG) while you are performing a decision-making task. Each of these sessions will last about 3 hours.

Neuropsychological testing may include tests of your memory, attention, concentration and thinking. We may ask you to be interviewed, complete questionnaires, take pen-and-paper or computerized tests and perform simple actions.

For the decision-making task, you will sit in a chair at a computer. Two symbols will be shown on the computer screen. You will have to choose one of the symbols as quickly as possible by clicking on a mouse button. Choosing one of the symbols will earn you money; the other will cause you to lose money. You will be told if you won or lost money only after you have made your choice. The total amount of money you won will be displayed at the top of the screen. You should try to win as much money as possible. This is a computer game and you will not actually win any payment. The decision making task will take about 30 minutes.

During the task, we will record the electrical activity of two muscles of your right arm using EMG. Small metal disks or sticky pad electrodes will be taped to the skin over the muscles that we choose. The electrodes will be removed after you have completed the task.

MEG is a procedure to record very small magnetic field changes produced by the activity of your brain. During MEG recording, you will be seated comfortably in the MEG recording room and a cone containing magnetic field detectors will be lowered onto your head. The recording will be made while you are seated in front of a computer screen, performing the visual motor reward task.

Study session # 3 (during surgery):
As part of your DBS surgery, the surgeon will need to make holes in your skull to implant the DBS electrodes deep in the brain. For research purposes, during the surgery after the holes have been placed, the surgeon will put a small strip of electrodes on the surface of your brain. The strip of electrodes may be placed on the brain surface on both sides of your brain. The electrodes will be used to record the activity of your brain cells while you are performing the decision making task and while you are resting. The strip of electrodes will be removed after you complete the task. The research part of the surgery will then be over. Placing the strip of electrodes and recording brain activity during the task will add about 30 minutes to your operation. Then the surgeon will complete your DBS surgery.

If you are a patient with Parkinson’s disease or Essential tremor, some of your medications, including Sinemet (carbidopa/levodopa), Stalevo (carbidopa/levodopa/entacapone), Requip (ropinirole) and Mirapex (pramipexole) may interfere with the results of the imaging tests or studies during surgery. You will be asked to stop your medications the night before visits 2, 3, 4 and 5. During deep brain stimulation surgery, the medications may interfere with our evaluation of your symptoms. Stopping your medications before visits 2,4, and 5 will allow us to replicate your clinical condition during surgery in visit 3. The brief discontinuation of medication is usually done overnight to minimize discomfort. You will be off of your medications for about 12 hours. You will be able to take the medications again after the MEG or surgery procedure is completed.

Risks, Inconveniences and Discomforts
Research recording during surgery: Having the strip of electrodes placed on your brain and the extra 30 minutes of surgical time for the research tests may slightly increase the risk of infection beyond the infection risk of 3-4% for DBS surgery itself. Moreover, the risk of bruise to the brain surface or subdural hematoma (bleeding between the brain and the skull) is noted with placement of a subdural electrode strip. If a subdural hematoma is observed following surgery, this will be monitored closely with repeat head scans. If a subdural hematoma is associated with significant pressure on the brain or shift of the brain from its normal position, a surgery (which includes removal and replacement of a portion of your skull) will be performed to remove the blood.

Withholding medications in patients with movement disorders:
Withholding your medications for Parkinson’s disease or Essential tremor can make your symptoms such as tremor or freezing worse. If being off your medications for 12 hours is known to significantly worsen your symptoms, you can be admitted to Suburban Hospital or NIH Clinical Center the night before the visits for monitoring. Of note, you should not stop taking your medications without first speaking with your prescribing physician. If you are hospitalized at Suburban hospital the night before surgery, your insurance provider will be billed; however, you may be responsible for co-payment or deductible charges.

History, neurological examination, MEG, and decision-making task: There are no medical risks associated with these procedures.

Neuropsychological tests are not harmful, but may be frustrating or stressful. We only ask that you try your best. No one performs perfectly on these tasks. You may refuse to answer any question or to stop a test at any time and for any reason.

MRI: People are at risk for injury from the MRI magnet if they have pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments. Welders and metal workers are also at risk for injury because of possible small metal fragments in the eye of which they may be unaware. You will be screened for these conditions before having any scan, and if you have any, you will not receive an MRI scan. If you have a question about any metal objects being present in your body, you should inform the staff. In addition, all magnetic objects (for example, watches, coins, jewelry, and credit cards) must be removed before entering the MRI scan room.

It is not known if MRI is completely safe for a developing fetus. Therefore, all women of childbearing potential will have a pregnancy test performed no more than 24 hours before each MRI scan. The scan will not be done if the pregnancy test is positive.

People with fear of confined spaces may become anxious during an MRI. Those with back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. Everyone having a research MRI scan will be fitted with hearing protection. Please notify the investigators if you have hearing or ear problems. You will be asked to complete an MRI screening form for each MRI scan you have. There are no known long-term risks of MRI scans.

Potential Benefits
There is no benefit to you from participating in this research study. However, we hope to learn more about brain activity in Parkinson’s disease and Essential tremor, which might help others in the future.

Right of Withdrawal and Conditions for Early Withdrawal
You may withdraw from the study at any time and for any reason without loss of benefits or privileges to which you are otherwise entitled. We can remove you from the study at any time if we think that continuation is not in your best medical interest or if you are unable to comply with the requirements of the study.

Results From this Study
The information we obtain from this study will not provide information on your health. You will not receive any individual results from the testing sessions or brain recording. Your results will be compared to decision-making task performance and MEG recordings from healthy volunteers participating in a similar NIH protocol.

Alternatives to Participation
The alternative to participating in this study is to have the DBS surgery without any of the research procedures.

Compensation and Travel costs
You will not be compensated for your participation and transportation will not be provided. Moreover, the costs of the above research procedures, including the strip electrodes, will not be passed on to you or your insurance provider.

Posting of Research Results on www.ClinicalTrials.gov
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required by U.S. Law. This web site will not include information that can identify you. At most the Web site will include a summary of the results. You can search this website at any time.

OTHER PERTINENT INFORMATION

  1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, the people who take part are not named and identified. In most cases, the NIH will not release any information about your research involvement without your written permission. However, if you sign a release of information form, for example, for an insurance company, the NIH will give the insurance company information from your medical record. This information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance.
    The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you should know that the Act allows release of some information from your medical record without your permission, for example, if it is required by the Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation organizations.
  2. Policy Regarding Research-Related Injuries.. In general, no long-term medical care or financial compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center or the Federal Government regardless of where the research is conducted. However, you have the right to pursue legal remedy if you believe that your injury justifies such action.
    Medical Faculty Associates, Inc., Suburban Hospital, and The George Washington University do not have programs to provide payment for long-term injuries or medical care or financial compensation for research-related injuries regardless of where the research is conducted.
    Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies. In general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of travel and subsistence will be offered consistent with NIH guidelines.
  3. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research participant, or about any research-related injury, contact the Principal Investigator, Dr. Mark Hallett; building 10, room 7D37, telephone: 301-496-5528. Other researchers you may call are: Dr. Donald Shields, of Medical Faculty Associates, Inc. at 202-741-2750.
  4. You may also call the Clinical Center Patient Representative at 301-496-2626 or the Suburban Hospital Ombudsman, Dr. Theodore Abraham at 401-502-7974. The George Washington University Office of Human Research is available at (202) 994-2715.
  5. Consent Document. Please keep a copy of this document in case you want to read it again.

Please see CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY (pdf) for full documentation and consent document.

Analysis of Visual-Motor Task Electrophysiological Activity During Deep Brain Stimulation for Treatment-Resistant Movement Disorders Study

INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH) and Suburban Hospital.

First, we want you to know that:

Taking part in NIH research is entirely voluntary.

You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking part in a study or be under evaluation for study participation.

You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.

Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH doctors or research team before you agree to the study.

Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other health professional.

Purpose of This Study
The aim of this study is to better understand activity in particular areas of the brain that might be involved in Parkinson’s disease and Essential tremor, and how the activity may change after deep brain stimulation (DBS) surgery in these disorders.

Facts That Led us to This Study
Previous research has shown what areas of the brain might be involved in symptoms of Parkinson’s disease and Essential tremor. This research has led to the use of DBS to treat these conditions. Some of the brain areas that might not function properly in people with these disorders are also involved in making decisions. To learn more about these brain areas, we will use a test that involves decision making to study brain cell activity before, during and after DBS surgery for these conditions. We will look at brain activity before and after surgery using a technique called magnetoencephalography (MEG). We will look at brain activity during surgery by recording directly from the surface of the brain.

Study Population
6 people with Parkinson’s disease, and 6 people with Essential tremor will participate in this study.

Inclusion Criteria
To be eligible to participate in this study, you must:

  1. Be at least 18 years old and have been diagnosed with Parkinson’s disease or Essential tremor.
  2. Be scheduled to have DBS for your condition.

Exclusion Criteria
You may not be eligible for this study if you:

  1. Have untreated depression or another psychiatric disorder
  2. Use illegal drugs
  3. Are pregnant
  4. Are uncomfortable in small, closed spaces (are claustrophobic)
  5. Have any metal in your body that would make having an MRI scan unsafe or would interfere with the MRI scan such as: cardiac pacemaker; implanted cardiac defibrillator; aneurysm clip; neuro or bone stimulator; insulin or infusion pump; implanted drug infusion device; cochlear, otologic, or ear implant; prostate radiation seeds; IUD (intrauterine device); transdermal nitroglycerin patch; any type of prosthesis (eye, penile); heart valve prosthesis; shunt (spinal/intraventricular); wire sutures or surgical staples; bone/joint pin, screw, nail, plate; body tattoos or makeup (eyeliner/lip); body piercing that cannot be removed; breast tissue expander; or other metal

Procedures
Study overview:

This study requires 5 study sessions over several months. The first 2 sessions will be in the NIH outpatient clinic before your surgery. The 3rd session will be during your surgery at Suburban Hospital. The 4th and 5th sessions will be at NIH, 3 and 6 months after your surgery.

Study session #1:
During the first study visit, we will ask you about your medical history and perform a neurological examination. Women who are able to get pregnant will have a pregnancy test. You will not be able to participate if you are pregnant. You will also have an MRI scan of your brain. This visit will last about 3 hours.

MRI uses a strong magnetic field and radio waves to take pictures of your brain. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. During the MRI scan, you will lie on a table that can slide in and out of the cylinder. You will be in the scanner about 20 minutes. While in the scanner you will hear loud knocking noises and you will be fitted with earplugs or earmuffs to muffle the sound. You can communicate with the MRI staff at all times during your scan, and you may ask to be moved out of the machine at anytime.

Study sessions #2, #4 and #5:
Study session #2 will be no more than 6 weeks before your surgery. Study session #4 will be 3 months after your surgery, and session #5 will be 6 months after surgery. During each of these visits we will conduct neuropsychological testing that will include standard assessment scales. We will record the activity of your brain using magnetoencephalography (MEG) while you are performing a decision-making task. Each of these sessions will last about 3 hours.

Neuropsychological testing may include tests of your memory, attention, concentration and thinking. We may ask you to be interviewed, complete questionnaires, take pen-and-paper or computerized tests and perform simple actions.

For the decision-making task, you will sit in a chair at a computer. Two symbols will be shown on the computer screen. You will have to choose one of the symbols as quickly as possible by clicking on a mouse button. Choosing one of the symbols will earn you money; the other will cause you to lose money. You will be told if you won or lost money only after you have made your choice. The total amount of money you won will be displayed at the top of the screen. You should try to win as much money as possible. This is a computer game and you will not actually win any payment. The decision making task will take about 30 minutes.

During the task, we will record the electrical activity of two muscles of your right arm using EMG. Small metal disks or sticky pad electrodes will be taped to the skin over the muscles that we choose. The electrodes will be removed after you have completed the task.

MEG is a procedure to record very small magnetic field changes produced by the activity of your brain. During MEG recording, you will be seated comfortably in the MEG recording room and a cone containing magnetic field detectors will be lowered onto your head. The recording will be made while you are seated in front of a computer screen, performing the visual motor reward task.

Study session # 3 (during surgery):
As part of your DBS surgery, the surgeon will need to make holes in your skull to implant the DBS electrodes deep in the brain. For research purposes, during the surgery after the holes have been placed, the surgeon will put a small strip of electrodes on the surface of your brain. The strip of electrodes may be placed on the brain surface on both sides of your brain. The electrodes will be used to record the activity of your brain cells while you are performing the decision making task and while you are resting. The strip of electrodes will be removed after you complete the task. The research part of the surgery will then be over. Placing the strip of electrodes and recording brain activity during the task will add about 30 minutes to your operation. Then the surgeon will complete your DBS surgery.

If you are a patient with Parkinson’s disease or Essential tremor, some of your medications, including Sinemet (carbidopa/levodopa), Stalevo (carbidopa/levodopa/entacapone), Requip (ropinirole) and Mirapex (pramipexole) may interfere with the results of the imaging tests or studies during surgery. You will be asked to stop your medications the night before visits 2, 3, 4 and 5. During deep brain stimulation surgery, the medications may interfere with our evaluation of your symptoms. Stopping your medications before visits 2,4, and 5 will allow us to replicate your clinical condition during surgery in visit 3. The brief discontinuation of medication is usually done overnight to minimize discomfort. You will be off of your medications for about 12 hours. You will be able to take the medications again after the MEG or surgery procedure is completed.

Risks, Inconveniences and Discomforts
Research recording during surgery: Having the strip of electrodes placed on your brain and the extra 30 minutes of surgical time for the research tests may slightly increase the risk of infection beyond the infection risk of 3-4% for DBS surgery itself. Moreover, the risk of bruise to the brain surface or subdural hematoma (bleeding between the brain and the skull) is noted with placement of a subdural electrode strip. If a subdural hematoma is observed following surgery, this will be monitored closely with repeat head scans. If a subdural hematoma is associated with significant pressure on the brain or shift of the brain from its normal position, a surgery (which includes removal and replacement of a portion of your skull) will be performed to remove the blood.

Withholding medications in patients with movement disorders:
Withholding your medications for Parkinson’s disease or Essential tremor can make your symptoms such as tremor or freezing worse. If being off your medications for 12 hours is known to significantly worsen your symptoms, you can be admitted to Suburban Hospital or NIH Clinical Center the night before the visits for monitoring. Of note, you should not stop taking your medications without first speaking with your prescribing physician. If you are hospitalized at Suburban hospital the night before surgery, your insurance provider will be billed; however, you may be responsible for co-payment or deductible charges.

History, neurological examination, MEG, and decision-making task: There are no medical risks associated with these procedures.

Neuropsychological tests are not harmful, but may be frustrating or stressful. We only ask that you try your best. No one performs perfectly on these tasks. You may refuse to answer any question or to stop a test at any time and for any reason.

MRI: People are at risk for injury from the MRI magnet if they have pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments. Welders and metal workers are also at risk for injury because of possible small metal fragments in the eye of which they may be unaware. You will be screened for these conditions before having any scan, and if you have any, you will not receive an MRI scan. If you have a question about any metal objects being present in your body, you should inform the staff. In addition, all magnetic objects (for example, watches, coins, jewelry, and credit cards) must be removed before entering the MRI scan room.

It is not known if MRI is completely safe for a developing fetus. Therefore, all women of childbearing potential will have a pregnancy test performed no more than 24 hours before each MRI scan. The scan will not be done if the pregnancy test is positive.

People with fear of confined spaces may become anxious during an MRI. Those with back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. Everyone having a research MRI scan will be fitted with hearing protection. Please notify the investigators if you have hearing or ear problems. You will be asked to complete an MRI screening form for each MRI scan you have. There are no known long-term risks of MRI scans.

Potential Benefits
There is no benefit to you from participating in this research study. However, we hope to learn more about brain activity in Parkinson’s disease and Essential tremor, which might help others in the future.

Right of Withdrawal and Conditions for Early Withdrawal
You may withdraw from the study at any time and for any reason without loss of benefits or privileges to which you are otherwise entitled. We can remove you from the study at any time if we think that continuation is not in your best medical interest or if you are unable to comply with the requirements of the study.

Results From this Study
The information we obtain from this study will not provide information on your health. You will not receive any individual results from the testing sessions or brain recording. Your results will be compared to decision-making task performance and MEG recordings from healthy volunteers participating in a similar NIH protocol.

Alternatives to Participation
The alternative to participating in this study is to have the DBS surgery without any of the research procedures.

Compensation and Travel costs
You will not be compensated for your participation and transportation will not be provided. Moreover, the costs of the above research procedures, including the strip electrodes, will not be passed on to you or your insurance provider.

Posting of Research Results on www.ClinicalTrials.gov
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required by U.S. Law. This web site will not include information that can identify you. At most the Web site will include a summary of the results. You can search this website at any time.

OTHER PERTINENT INFORMATION

  1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, the people who take part are not named and identified. In most cases, the NIH will not release any information about your research involvement without your written permission. However, if you sign a release of information form, for example, for an insurance company, the NIH will give the insurance company information from your medical record. This information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance.
    The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you should know that the Act allows release of some information from your medical record without your permission, for example, if it is required by the Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation organizations.
  2. Policy Regarding Research-Related Injuries.. In general, no long-term medical care or financial compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center or the Federal Government regardless of where the research is conducted. However, you have the right to pursue legal remedy if you believe that your injury justifies such action.
    Medical Faculty Associates, Inc., Suburban Hospital, and The George Washington University do not have programs to provide payment for long-term injuries or medical care or financial compensation for research-related injuries regardless of where the research is conducted.
    Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies. In general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of travel and subsistence will be offered consistent with NIH guidelines.
  3. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research participant, or about any research-related injury, contact the Principal Investigator, Dr. Mark Hallett; building 10, room 7D37, telephone: 301-496-5528. Other researchers you may call are: Dr. Donald Shields, of Medical Faculty Associates, Inc. at 202-741-2750.
  4. You may also call the Clinical Center Patient Representative at 301-496-2626 or the Suburban Hospital Ombudsman, Dr. Theodore Abraham at 401-502-7974. The George Washington University Office of Human Research is available at (202) 994-2715.
  5. Consent Document. Please keep a copy of this document in case you want to read it again.

Please see CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY (pdf) for full documentation and consent document.

Essential Tremor Clinical Research Hope for the Future Conference

Oct 20, 2012 – Fort Belvoir, VA.  As the conference title suggests, this gathering was intended to give hope to those with essential tremor (ET), a condition estimated to affect a high number of Americans, approximately 10 million according to recent literature. There are likely many more who do not know they have it perhaps attributing their shaking hands to being nervous. They may attempt to control it and hide it, rather than seek treatment from a neurologist or more specifically a movement disorder specialist.

There were sixty-two in attendance mostly from area ET support groups in Silver Spring and Columbia, MD and Falls Church and Landsdowne, Virginia. The conference speakers were Dr. Codrin Lungu (Deputy Clinical Dir of Clinical Research), who runs the Parkinson’s Clinic and the medical side of the Deep Brain Stimulation (DBS) program at the National Institute of Neurological Disorders & Stroke; Dr. Claudia Testa (Associate Director Clinical Care and Research, Virginia Commonwealth University, Parkinson’s & Movement Disorders Center); and Dr. Mark Hallett (Chief, Motor Control Section, NINDS).

Peter Muller, Executive Director of HopeNET, a foundation working to increase awareness of ET, gave the opening remarks and let us know the latest about a fairly new procedure called MRI Focused Ultrasound. The University of Virginia did a pilot trial in 2011 whereby mri focused ultrasound surgery was performed on fifteen patients and it must have been seen as a success as evidenced by the 6000 on the waiting list for the procedure. Muller expressed excitement for this technology and introduced Jessica Foley, Scientific Director of the Focused Ultrasound Society. He also introduced Deb Zeller, the President of the Virginia School Nurses Association. HopeNET is jointly working with Ms Zeller on a project to develop a Careplan for use by school nurses with children who have ET.

Muller has been instrumental in bringing people with the condition closer to the medical community in a search for treatment, therapies and ultimately a cure, first in his position as a Community Ambassador to the International Essential Tremor Foundation and now for HopeNET. Muller told the group about the series of surveys being conducted by HopeNET and Tremor Action Network to answer questions on the various symptoms and treatments for ET. The last survey in French was sent to 1400 in France, Belgium and Quebec, Canada.

The first speaker, Dr. Lungu, explained in detail the procedure deep brain stimulation (DBS), a surgical option for those with significant tremor that does not respond to medication. DBS was first performed on an ET patient but now is more often used for another more well-known movement disorder, Parkinson’s Disease. DBS is “electrical therapy” for tremor and is like a pacemaker for the brain that intervenes and normalizes the electrical signals thrown off by disease, as Lungu explained it. DBS is brain surgery that involves drilling two holes in the skull the size of a dime and running electrodes to the deep structures of the brain to block the abnormal signals at the thalamus. The wires run from the thalamus (at a point called the vim) down under the skin behind the ear, down the neck and meets a small battery pacemaker in front of the chest from which the voltage and frequency are chosen. Dr. Lungu made it clear that this surgery ‘is the process, not the event,’ as he said one of his colleagues puts it. The event is the 24/7 adjustment of the electrical stimulation from the pacemaker. There are exclusion criteria for DBS – generally healthy candidates should elect this surgery and those without depression because DBS could make it worse. People also need to know what to expect. For example, the problem is still there after DBS, it is just being covered up symptomatically. DBS has its imperfections such as the fact that the motor part of the brain is separated into left brain and right brain meaning that DBS has to be done one side at a time. The dominant side is often the side done. If a person elects to have both sides done Dr. Lungu prefers to do both sides at once rather than one side now and the other side at a later surgery. He went over the risks of the surgery and the side effects, such as very mild verbal fluency issues, and subtle balance issues.

One attendee suggested getting ET listed in items asked about in the National Health Interview Survey that the Nat’l Center for Health Statistics conducts or the Health & Nutrition Examination Survey.

Dr. Testa spoke about clinical research using genetic research to give people a better understanding of the process. Clinical research as a term means working with people to study human disease. There are clinical trials in which a new intervention is tested in people, observational trials where researchers don’t try to intervene but observe only, and then there are trials dealing with parts of people, such as blood and saliva samples to get DNA for those studies. Where do research questions come from? The researchers think about basic biology of the brain and come up with ideas, and there’s community-based research, such as the surveys HopeNET has been conducting. A VCU neuropsychologist is presently doing a needs-based survey for movement disorders that will help determine ideas on ways to proceed. ET affected individuals are encouraged to participate. Understanding disease in people means looking at the mechanisms of how things work, and then the treatments that need to be developed.

An example of traditional research, called epidemiology, studies large groups of people. A famous one is the Framingham, Mass study consisting of the entire town’s population and has been studied for forty years. The resulting information has been used to find risk factors for heart disease and others. There have also been door-to-door surveys for ET (an epidemiologist and neurologist together that examined people on the spot) in places like Turkey and Spain. In those communities four percent of those over 40 years of age were found to have ET. Another example of working with people deals with looking at the brain to understand the mechanisms involved such as imaging, MRIs or functional scans looking at blood flow. Also the brain banks at Columbia University in NY and at the Arizona Study of Aging and Neurodegenerative Disorders, study the brains donated by people with ET. Research papers from these studies have only been coming out in the past few years. VCU, where Testa works, houses the MidAtlantic Twin Registry, “an amazing resource,” she says in her genetic studies and how they play a role in ET.

Testa explained, “We don’t know of a single gene mutation that causes ET.” A lot of research has been done on the connection between a change in the gene and disease. She spoke about establishing linkages across families using DNA. She explained how the Lingo-1 gene discovered to play a role in ET, does not make protein which implies it doesn’t code (for protein) so there is more work to do to discover details about that interon area – without proteins it is more difficult to study. Testa explained the genome and the detailed clues it might hold.

Our next speaker was Dr. Mark Hallett started his talk by emphasizing people’s participation in research studies since there haven’t been many good animal models. He said trying to address the basic pathophysiology or cause of ET is necessary if a rational treatment is to be created.  We still don’t understand where ET comes from so genetics is an important area to study. Hallett is of the opinion that ET is not a single entity but multiple different entities, meaning a family of diseases, which may be why it’s been difficult to find a single gene that is underlying it.  Hallett explained there may be different types of ET, meaning different pathophysiologies and different therapies. In other words, ET may look the same in two different people on the outside but be different on the inside. When it comes to ET responsiveness to alcoholic beverages, some people respond with a reduction of tremor and others do not – which may be an indicator of ET subtypes. Hallett asked for a show of hands about people’s responsiveness to alcoholic drinks, in that they show an improvement in tremor when drinking alcohol. The majority of the audience raised their hands. Alcohol also can have a rebound effect, he said, whereby once it wears off the tremor returns worse, temporarily.

The Movement Disorder Society is the international society of mostly neurologists, and it has taskforces looking into different types of tremor. Hallett is on a taskforce to come up with better definitions of ET and differentiate its subtypes. Hallett went over the few drugs on the market that help ET. Primidone and beta blockers are the two most common. Sometimes they work for a while and wear off. Some anticonvulsant medicines have benefit: gabapentin, topiramate and others. He said that there is not much work going on in the active development of other drugs for ET. Before he came to the conference today he checked the clinicaltrials.gov website to see what clinical research is being done in the world, and at the moment there are zero – as in no clinical trials being done in the area of ET research. The pipeline needs to be stimulated in this regard.

He gave us the alcohol or octanol story to give a sense of what the process of drug development is like at the NIH. He cited Rodolfo Llinas, a neuroscientist who studied longer chain alcohols and patented them all – saying they would be good for treating any tremor. Octanol worked better in the animal studies than ethanol did. Octanol (an 8 carbon atom) was found to be one of the best longer chain alcohols for the condition and through studies at the NIH they realized that the octanol is metabolized or broken down in the blood  into octanoic acid. How many carbons is best is the question. These studies on octanol and octanoic acid at NIH have taken about 10 years to complete. NIH received a “use patent” to support development. With a pharmaceutical company, NIH started the clinical trial process. Hallett went on to explain that the cost to do an animal toxicology test and to safely try it in humans runs approximately one million dollars. It is difficult to develop a pharmaceutical. The conclusions show that octanol was efficacious to a certain extent, without people getting drunk. At a minimum, it will take several more years for the FDA to approve octanoic acid as a drug. Octanoic acid is a component of the ketogenic diet, a special diet mostly consisting of fat given to children with very severe epilepsy. Someone discovered this diet could help and it’s been used for years. A challenge is how to administer it. It tastes terrible so time needs to be spent encapsulating it. One attendee mentioned to Dr. Hallett that long periods of fasting has helped improve his tremor. Hallett explained that when you fast, your body’s metabolism changes more toward energy from ketones than from sugars. You are converting your body metabolism to a state similar to someone on a ketogenic diet.

Hallett suggested that the alcohol interfering with the calcium channel story may not be right for explaining ET and that maybe a GABA abnormality is a better model for ET than the harmaline animal study model. Another clinical trial from France involves transcranial magnetic stimulation (TMS), external stimulation over the cerebellum that reduced the severity of tremor for a period of time. TMS was given daily for 5 days and the efficacy was for 3 months. TMS has been approved for one type of depression, refractory depression.

Questions were asked of the 3 doctors at the end of the conference. Hallett talked about how relaxation and reducing anxiety and stress help to improve tremor. The hormone, cortisol, in the body is released in response to anxiety and stress and causes the brain to shrink! Dr. Testa talked about observations of the community – the changes in anxiety for people with ET as compared with those without it. There’s a powerful pathway between the unconscious mind and mood states as well as really strong symptoms in the body. Dr. Testa suggested that maybe ET patients experience more anxiety symptoms as a result of the ET. Dr. Lungu concurred that it’s unclear whether the anxiety is part of the biological condition of the disease. Dr. Hallett was asked if there is a connection between epilepsy and ET. He responded that the pathophysiology of epilepsy is well-known. Nothing at any level, at the cellular level, at the thalamus, through EEG or neuroimaging shows a connection. In answer to the question why do the anticonvulsants like primidone, gabapentin and others work for ET, Dr Hallett said these drugs all have multiple effects but we do not know how. Dr. Hallett believes that since the prevalence of ET is high, he thinks pharmaceutical companies should be more interested in developing drugs for it. Dr. Testa said the epidemiology studies indicate age of onset is in general in older adults. Hallett said that patients can help by going to their congressman to say ET is an important concern, and there are a lot of us with the condition.  Joan Marie Barringer, the Support Group Leader from Vero Beach, Florida brought up the DSM Diagnostic Statistic Manual that says many of those with tremor have social phobia.

Conference attendees were pleased with the cooperation of the local medical community at places like NIH and VCU in communicating their expertise, thoughts and findings to the ET community.

Lisa Gannon
Silver Spring Support Group