Join us at this Thursday’s ET support group in Silver Spring, Maryland

Please note this meeting starts at 3pm, not the regular 10:30am time. Dr. Dietrich Haubenberger of NIH will speak about the current status of ET research.  He has spoken previously to our group. To say he is an expert on the subject is an understatement.  You won’t want to miss this meeting!

 

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.

Big McGill University Study Underway – Now Recruiting Those With Essential Tremor

One of our Falls Church, Virginia ET support group members has signed up for and made us aware of this very large genetics study in Montreal, Quebec, Canada. It comes on the heels of an exciting large genome-wide association study (GWAS) conducted by researchers at Montreal Neurological Institute and Hospital and Kiel University in Germany and written about in Brain, as detailed in the article. Click article link for more details …

https://www.mcgill.ca/channels/news/essential-tremor-sufferers-needed-groundbreaking-study-263594

ET Insights from Dr. Claudia Testa

On December 6th, I met with Dr. Claudia Testa of the Virginia Commonwealth University’s Parkinson’s & Movement Disorder Center. She is one of the foremost experts on genetics concerning Essential Tremor (ET). She told me that there is a good possibility that ET is not caused by a single change in a single gene. This means there is not one mutated “ET gene” that can just be corrected. Instead, there are probably many different genetic changes that add up to ET. This highlights the challenges faced by those doing the research regarding ET. The longer I am the Executive Director of HopeNET, the more I appreciate the challenges faced by these researchers. As I have said many times, the brain is the most complex object known to man.

However there is good news that should help the research process. First of all, many researchers are taking the approach of not labeling patients but rather grouping them according to the symptoms they share. In other words, not simply grouping those with ET or Dystonia but rather, those with severe hand tremor, voice tremor and problems with balance – for example.

Another positive development is the desire to have Common Data Elements (CDE) for ET. Quite simply, this would help ensure that researchers compare apples to apples & oranges to oranges.

The picture in creating better treatments and ultimately a cure is daunting. But the picture has never looked better than it does now. There is hope.

– Peter

Speech to Text Technology Writes for You

microphone-clipart-9tpekegncIn the early 1990s, a number of companies started to offer software that was designed to convert spoken words into text that could then be displayed or printed. Among the early commercial offerings was a program entitled “Dragon Naturally Speaking”. In 1994, I tried an early version of Dragon in my workplace. After installing a microphone to my computer, I spoke several sentences rather slowly, and watched words appear on the computer monitor. Unfortunately, there were quite a few errors in the written text, and I chose to stick with keyboard entry.

Now, more than two decades later, Dragon NaturallySpeaking has been improved such that for many users with hand tremors (from E.T., Parkinson’s Disease, Dystonia, and other causes) it performs well enough that it can serve as a person’s primary method for entering text into a computer.

Most modern cell phones offer users the option to speak into their phone to generate an email, a text message (or iMessage), a memo, or a variety of other “text” inputs. Those with iPhones (the iPhone 4s or newer) or iPads can ask “Siri” a wide variety of questions by voice. Many newer automobiles are capable of responding to driver voice commands (tune radio to FM 107.9; turn on air conditioning, call home, etc.). The number of “things” that can respond to human voice commands continues to grow. All of these capabilities rely on speech recognition technology.

— Fred Berko

Dr. Dietrich Haubenberger of NINDS/NIH Gives Presentation On ET Outlook

title-page-et2016-presentationWhen we founded HopeNET 5 years ago, we felt that the thing that the ET community needed most at that time was HOPE – hence the name. In the meantime, we have strived hard to bring some hope to all with ET. Accordingly, HopeNET played a key role in having the ET conference at NIH in May 2015. Since that conference, there has been a big increase on the part of industry in developing new treatments for ET. Dr. Dietrich Haubenberger of NIH is probably in the best position to know what is going on with ET. He came to the Falls Church, Virginia ET support group on October 14th and made the attached presentation, Essential Tremor 2016: A look into the pipeline. There has never been a better time than right now for hope – for all of us in the ET community.

— Peter

Outstanding UMD Team Who Performed MRI Focused Ultrasound To Treat Essential Tremor

The picture in the following article contains a number of people who were part of the outstanding team who performed the MRI Focused Ultrasound procedure on me:

Charlene Aldrich – who was beside me the entire time except when the sonications were happening; Dr. Howard Eisenberg – the neurosurgeon; Dr. Paul Fishman – the neurologist; Dr. Deeraj Gandhi – the radiologist; Pam Janocha; Erma Owens; Mor Dayan – Insightec (not pictured)

There were others. As a result of the Ativan and many things occurring simultaneously, I was not aware of them.

Everybody acted professionally and as a team!

— Peter


University of Maryland Center of Excellence Dedicated to Brain Research

In recognition of their leadership in advancing focused ultrasound research for the brain, the Foundation is pleased to designate the University of Maryland as a Center of Excellence.

 umdcoeteam
Maryland’s “Brain Trust”
(R to L) Front: Dr. Victor Frenkel, Dr. Graeme Woodworth, Kaitlyn Henry,
Charlene Aldrich, Dr. Howard Eisenberg Middle: Andy Hebel, Dr. Paul Fishman,
Dr. Elias Melhem, Dr. Deeraj Gandhi Back: Liz Rolon, Dr. Rao Gullapalli, Pam Janocha,
Erma Owens

The Chair of the Department of Neurosurgery, Howard Eisenberg, MD, and Chair of Diagnostic Radiology and Nuclear Medicine, Elias Melhem, MD, are managing a comprehensive bench-to-bedside program expanding the technology’s neurosurgical capabilities as well as innovating new methods for delivering therapies to the brain.

“The University of Maryland has created a dream team of experts in neurosurgery, neuroradiology, neurology, and biophysics that is collaborating to establish new frontiers to optimize the technology to treat a range of neurologic and psychiatric disorders,” says Foundation Chairman Neal F. Kassell, MD.

Both Eisenberg and Melham have a long-standing interest in focused ultrasound (FUS). Dr. Eisenberg had served as a consultant to the Foundation for over a decade. Dr. Melhem initially became aware of FUS when he was at the University of Pennsylvania and heard Ferenc Jolesz give a talk about 10 years ago. “This really captured my imagination for the potential of the technology,” says Melhem. He was not able to obtain a system at Penn, but as he was being recruited to be Chairman of the Radiology Department at Maryland in 2012, he solicited support from the Dean of the School of Medicine to invest in creating a hub for focused ultrasound research. Since then he has invested in an Insightec Exablate clinical platform and basic science systems. The Departments of Radiology, Neurology and Neurosurgery have collaborated to create a multidisciplinary team of experts that has attracted more than $500,000 in research grants to date and laid a pipeline for future funding.

Clinical Program

Maryland has been a top site for recruiting patients into essential tremor (ET) and Parkinson’s disease clinical trials through the leadership of Drs. Melhem and Eisenberg, along with neurologist Paul Fishman, MD, PhD, and research coordinator Charlene Aldrich, who is credited for being an extremely effective ambassador to the patient community. The FUS clinical center at Maryland is conveniently located within the hospital with a new dedicated MRI scanner, its own prep area, waiting room, and recovery area.

“It is very fulfilling to be able to provide a less invasive option for patients – some just don’t want an electrode put into their brain,” says Dr. Eisenberg. With his neurophysiologic training, Dr. Fishman is a valuable member of the treatment team. He assesses patients and collaborates on the brain mapping before procedures, evaluates patients with each sonication, and afterwards conducts the follow-up visits.

Now that the Exablate system is approved to treat ET, the team looks forward to treating patients commercially. “We want to collaborate with other sites so we know where patients from certain regions of the country should go for treatment,” says Eisenberg.

Optimizing Clinical Treatment

The team is also looking forward to pushing the boundaries of ablation for movement disorders. “Now that we have established a foothold for unilateral ET, we want to expand the beachhead to explore treating the second side and retreating patients who may lose the effect,” says Fishman. “These questions are even more vital for Parkinson’s because the disease is commonly bilateral and more progressive.” See his July 2016 Foundation Webinar on Research Progress in Parkinson’s Disease and a Role For Focused Ultrasound.

There is agreement that a global registry is needed so sites can utilize common protocols and share insights into issues such as what types and symptoms of Parkinson’s are best served by ablating certain targets. “That is where the clinical research is heading, and it is very exciting to be on the leading edge of making these determinations,” says Fishman.

Breaking Through Barriers to the Brain

Maryland has a consolidated scientific research facility with two MRI scanners, a preclinical FUS system from Image Guided Therapy, a benchtop custom built animal system, and many ultrasound-based resources. They have seven faculty members involved from radiology, immunology, ultrasound biophysics, cancer biology, chemical and mechanical engineering, and neurosurgery.

Dr. Fishman is a bridge to the scientific team at Maryland. After decades in the lab developing experimental agents for neurodegenerative disorders, he collaborated with neurosurgeon and scientist Graeme Woodworth, MD, FUS biophysicist Victor Frenkel, PhD, and others to optimize the use of focused ultrasound to breach the blood-brain barrier (BBB) and deliver these types of therapies.

The team is making preclinical progress on drug delivery to the brain along several fronts. They are opening the BBB with FUS and utilizing magnets to direct magnetically labeled stem cells to targeted areas in the brain. Dr. Woodworth is working with the FDA to get clearance for a clinical study that would use FUS to open the BBB to deliver a dye to improve visualization within a brain tumor and to determine how deep small molecules can penetrate the brain.

“FUS could become the first clinically versatile way of introducing this enormous backlog of therapeutics that do not cross the blood-brain-barrier,” says Fishman. “If it works, this could alter the scientific and clinical landscape for treating the brain.”

Dr. Frenkel, from the department of Radiology, has created a custom portable system for studying FUS-mediated neuromodulation and is assessing how altering the microenvironment of the brain affects the inflammatory response and the movement of nanoparticles through neurological tissue. “There is a possibility that we can alter the natural history of some pretty devastating diseases,” says Woodworth. “We are just a year or two away from clinical trials.”

A Promising Future

The leadership is very optimistic about the potential for the technology and the impact of being a Center of Excellence. “This recognition will help to drive awareness across other departments that will open up doors for new collaborations leading to more novel ideas and better solutions to pursue,” says Eisenberg.

“Our achievements in focused ultrasound – both in terms of advancing the science and transforming clinical care – have been recognized by the Dean and our Board of Trustees,” says Melhem. “We are looking forward to continuing to demonstrate that we are a model for excellence in the field.”

Recently Published Work from the Maryland Team

Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, et al. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 2016 Aug 25;375(8):730-9.

Hersh DS, Kim AJ, Winkles JA, Eisenberg HM, Woodworth GF, Frenkel V. Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.Neurosurgery 2016 Aug 22.

Khanna N, Gandhi D, Steven A, Frenkel V, Melhem ER. Intracranial Applications of MR Imaging-Guided Focused Ultrasound. AJNR Am J Neuroradiol. 2016 Aug 18.

Hersh DS, Nguyen BA, Dancy JG, Adapa AR, Winkles JA, Woodworth GF, Kim AJ, Frenkel V. Pulsed ultrasound expands the extracellular and perivascular spaces of the brain.Brain Res. 2016 Sep 1;1646:543-50. doi: 10.1016/j.brainres.2016.06.040. Epub 2016 Jun 28.

Hersh DS, Wadajkar AS, Roberts NB, Perez JG, Connolly NP, Frenkel V, Winkles JA, Woodworth GF, Kim AJ. Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier. Curr Pharm Des. 2016;22(9):1177-93.

Tebebi PA, Burks SR, Kim SJ, et al. Cyclooxygenase-2 or tumor necrosis factor-alpha inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle.Stem Cells (Dayton, Ohio). Apr 2015;33(4):1173-1186.

Ziadloo A, Xie J, Frenkel V. Pulsed focused ultrasound exposures enhance locally administered gene therapy in a murine solid tumor model.J Acoust Soc Am Mar 2013;133(3):1827-1834.