Focused Ultrasound and the Blood-Brain Barrier

When does a barrier protect and when does it hinder? This question is central to the challenge of delivering therapeutics to the brain. For many neuropathologies, the answer is clear: there is a critical need for strategies that can allow clinicians to effectively deliver drugs to the brain. We believe focused ultrasound (FUS) has the potential to be a powerful tool in this quest.

Part of this challenge lies in the unique nature of the blood vessels in the brain. The cells that line these vessels are tightly linked together, creating a complex obstacle—called the blood-brain barrier (BBB)—that prevents the vast majority of drugs from entering the brain from the bloodstream. Throughout the years, several strategies of bypassing the BBB have been used, with limited success and many adverse effects. These range from directly inserting a needle into the brain for injections, to the administration of hyperosmotic solutions, which create gaps between cells in the BBB throughout a large volume.

In 1956, Bakay et al successfully ablated brain tumors using high-intensity FUS. In doing so, he observed that the permeability of the BBB was enhanced in the periphery of the ablated tissue. While this was exciting news for BBB enthusiasts, the necessity of damaging tissue in the process of opening the BBB was clearly unacceptable. Several decades later, this approach was successfully modified by administering microbubbles, an ultrasound contrast agent, before sonicating (Hynynen et al 2001). This made it possible to use much lower power levels to produce the desired increase in BBB permeability, thereby avoiding brain damage. By adjusting where the ultrasound energy is focused, specific brain regions can be targeted. For a few hours after treatment, drugs can be administered intravenously, bypass the BBB, and enter the neural tissue in the targeted areas.

Over the past 16 years, many preclinical studies have used FUS to increase the permeability of the BBB, delivering a wide range of therapeutic agents to the brain, from chemotherapeutics and viruses, to antibodies and stem cells. Efficacy has been demonstrated in models of Alzheimer’s disease, Parkinson’s, brain tumors, and others. Moreover, the safety of using FUS to increase BBB permeability has been tested in every commonly used laboratory animal.

The flexibility of FUS as a tool for treating neuropathologies may go beyond the delivery of drugs to the brain. Recently, FUS was shown to reduce the amount of β-amyloid plaques and improve memory deficits in the brains of transgenic mice (Burgess et al 2014, Leinenga and Gotz 2015, Jordao et al 2013).

The success of these preclinical trials has led to the initiation of 3 human trials. Two of these trials are testing the safety of increasing the permeability of the BBB in brain tumors for chemotherapy delivery, and the third is evaluating the safety and initial effectiveness of FUS in patients with early stage Alzheimer’s disease. The rapid movement towards clinical testing has been accompanied by impressive technological advancements in the equipment used to focus ultrasound through the human skull. Arrays of thousands of ultrasound transducers can be controlled to produce sound waves that travel through bone and brain, and arrive at precisely the same time in the targeted location. The sound produced by vibrating microbubbles can be detected and used to ensure the treatment is progressing as planned.

If the barrier to drug delivery to the brain can be bridged by FUS, the development of effective treatment strategies for a wide range of neuropathologies will expand. Given the clear need for such treatments and the flexibility of FUS, the recent push toward clinical testing is encouraging. The coming years will be critical in demonstrating the safety of the technique and spreading awareness. Success in these regards will go a long way in establishing FUS as an impactful tool in the fight against inflictions of the central nervous system.

 

If you deliver drugs to the brain, how do you do so? Have you found a way to permeate the blood-brain barrier using ultrasound? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Charissa Poon and Dallan McMahon are PhD students at the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and the department of Medical Biophysics, University of Toronto, respectively.

Kullervo Hynynen, PhD, is professor at the department of Medical Biophysics and the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and a senior scientist at Sunnybrook Research Institute in Toronto, Canada.

Internal Medicine and Bedside Ultrasound–A Match Made in Heaven

I am an internist who does bedside ultrasound. This has not always been true. From 1986, when I got my MD from Johns Hopkins School of Medicine, to November 2011, I was a traditional internist, taking care of a panel of patients in a small university town in Idaho. I saw my patients in the office when they could walk or wheel in with their problems and in the hospital when they were sicker. I took call for my partners on rotating weekends and holidays. I occasionally ordered ultrasounds and echocardiograms and thought of them as blurry representations of internal structures that could be magically interpreted by radiologists.

In 2011, events such as the growing up of our 2 children allowed me to reconsider my choices of what to do with my MD. I had always wanted to do medicine in resource-poor settings overseas. I had often been curious about locum tenens work in other states, which would involve adventure and exposure to new practice styles and surprisingly generous compensation compared to my predominantly outpatient practice. I also had an urge to binge on continuing medical education courses, which I had denied myself for years due to responsibilities at home.

Janice Boughton, MD

One of the CME courses I treated myself to was an introductory course in emergency ultrasound through Harvard/Massachusetts General Hospital. It was wonderfully taught and I was immediately hooked. Ultrasound at the bedside would transform my practice and had the potential to transform the whole practice of internal medicine! The Cupid of bedside ultrasound had sunk his arrow straight between my eyes.

I went on to take more courses in bedside ultrasound both in person and online and bought myself a small pocket ultrasound which rapidly developed my imaging skills. I began to use ultrasound clinically as a diagnostic tool within weeks of my first exposure. I discovered over-expanded bladders, failing hearts, pleural effusions, ascites, or lack thereof in my patients with big bellies. I became a better doctor, and enjoyed my job more. My patients were happy to have benefitted from what looked to them like Star Trek technology.

I expected at any point that someone in the diverse hospitals where I served as a locum tenens hospitalist would ask for my credentials or forbid me to use ultrasound. I expected skepticism by cardiologists with whom I worked. I expected radiologists to be upset at me. I even did a 1-month UC Irvine mini-fellowship and ARDMS certification as a sonographer. These experiences gave me a vast amount more expertise and confidence, but were mostly to ward off imagined disapproval. Yet nobody ever made me present my certification. Nobody disapproved to my face except one radiologist, who I’m still working on. Cardiology consultants were tickled to get imaging information in addition to history and vital signs. I may have benefitted from being in hospitals where people were too busy taking care of patients to fuss with me. It really seemed, though, that the vast majority of people with whom I worked realized that I was a better doctor with an ultrasound than without.

I have gone on to teach bedside ultrasound and participate in research on malaria and schistosomiasis with medical students in Tanzania. I have taught basic ultrasound to overburdened healthcare workers and physicians from Doctors Without Borders in South Sudan during its ongoing civil war. Knowing how to teach basic bedside ultrasound means I am valuable in resource poor settings even if I can only stay for a couple of weeks. I have been able to teach my internal medicine colleagues in the US along with residents and medical students, which has been a wonderful opportunity for a nonacademic rural physician.

So what’s my point here? As an “early adopter” of bedside ultrasound in internal medicine I have made myself a test case. So far these are the results:

  1. It wasn’t too hard to learn enough ultrasound to be a better doctor.
  2. There was never a time when I was too much of a novice to benefit from bedside imaging, yet every time I ultrasound a patient I learn something new. I can’t foresee a time when my learning will be complete.
  3. There has been surprisingly little push-back and a gratifying amount of appreciation.
  4. Bedside ultrasound is the perfect extension of the physical exam in internal medicine. It brought back my joy in physical diagnosis. We should all be doing it!

 

Have you used ultrasound in your internal medicine practice? Have you gone after ultrasound education after obtaining your degree? How can medical education be modified to encourage the widespread use of ultrasound by future internists? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Janice Boughton, MD, is an internist working as a staff Hospitalist at Gritman Medical center as well as is a locum tenens physician at other northwest hospitals. She also supervises and serves in rural health clinics, and blogs about bedside ultrasound and other issues at http://whyisamericanhealthcaresoexpensive.blogspot.com/?m=1.

The National Ultrasound Interest Group (NUSIG)

The National Ultrasound Interest Group (NUSIG) is a student-led organization founded in 2014 to promote ultrasound in undergraduate medical education. You may know us as the force behind planning national level events like SonoSlam. The bulk of NUSIG’s work, however, is sharing education and leadership resources between Ultrasound Interest Groups (USIGs) across the country. Each of the five regional representatives contact medical schools in their areas to exchange ideas, plan co-sponsored events, and see how NUSIG can assist them in evangelizing ultrasound.

SonoSlam_organizers

NUSIG provides everything from information on getting equipment and funding, to original educational content. Our podcast on iTunes (quickly closing on the 1,000 download mark) currently features a journal club series. Each episode is hosted by a different school evaluating an ultrasound-related article.

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Our next series is how to plan an Ultrafest, where we interview schools experienced in putting on these events. Our hope is that these USIGs can learn from each other, and other schools might be inspired to start their own UltraFest once it’s been laid out how. In the future, we aim to collect medical student level ultrasound lectures from across the country and publish them for anyone to view. Our vision is to serve as a central repository for the best medical student educational content available. Lastly, our twitter feed regularly features current ultrasound research articles, and retweets outstanding free open access medical education content.

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If you want to learn more about us or get involved, check out our website at www.nationalusig.com, and follow us on twitter and Facebook @NtlUSIG. You can find us on iTunes by searching for “NUSIG podcast.”

Are you a member of the National Ultrasound Interest Group? Did you attend this year’s SonoSlam? If so, share your thoughts and feedback. Comment below or let us know on Twitter: @AIUM_Ultrasound.

Mat Goebel is in charge of Social Media for the National Ultrasound Interest Group and is a medical student at University of California at San Diego.

Why SonoStuff.com?

Three reasons:

As a co-director of technology enabled active learning (TEAL) at the UC Davis school of medicine I incorporate important technologies into the medical curriculum, which has primarily been point of care ultrasound (POCUS). Ultrasound is an incredible medical education tool and curriculum integration tool. It can be used to teach, reinforce, and expand lessons in anatomy, physiology, pathology, physical exam, and the list goes on.

I knew there was a better way to teach medical students thaschick_photo_1n standing in front of the classroom and giving a lecture. Student’s need to learn hands-on, spatial reasoning, and critical thinking skills to become excellent physicians. Teaching clinically relevant topics with ultrasound in small groups with individualized instruction
is the best strategy. I needed to flip the classroom.

I started by creating online lectures for an introduction to ultrasound lecture, thoracic anatomy, and abdominal anatomy:

Introduction to Ultrasound, POCUS

FAST Focused Assessment of Sonography in Trauma Part 1

FAST Focused Assessment of Sonography in Trauma Part 2

Aorta Exam AAA POCUS

Introduction in Cardiac Ultrasound POCUS

Topics quickly grew in scope and depth. I initially housed my lectures on YouTube and emailed them out to students before the ultrasound laboratory sessions. However, I wanted a platform that allowed for improved organization and showcasing. I needed a single oschick_photo_2nline resource they could go to to find those materials I was making specific to their medical curriculum.

https://www.youtube.com/channel/UCOhSjAZJnKpo8pP7ypvKDsw

Around the same time, during a weekly ultrasound quality assurance session in my emergency department I realized we were reviewing hundreds of scans each month and the reviewers were the only ones benefiting educationally from the process. Many cases were unique and important for education and patient care.

We began providing more feedback to our emergency sonographers and I decided I could use the same software I was using to develop material for the school of schick_photo_3medicine to highlight the most significant contributions to POCUS in our department every week. I quickly realized I needed a resource to house all these videos, one that anyone in my department could refer to when needed. The most efficient and creative method was to start a blog. I was discussing the project and possible names for the blog with colleagues and Dr. Sarah Medeiros said, “sounds like it’s a bunch of ultrasound stuff”. https://sonostuff.com was born.

I owe a great deal to free and open access to medical education or FOAMed. I was hungry for more POCUS education in residency and the ultrasoundpodcast.com came to the rescue. I became a local expert as a resident and even traveled to Tanzania to teach POCUS.

schick_photo_4I primarily began www.SonoStuff.com to organize and share with my department of emergency medicine and school of medicine, but it grew into a contribution to the growing body of amazing education resources that is FOAMed. I now use it as a resource in my global development work along with the many other FOAMed resources.

The work we all do in FOAMed, including AIUM’s the Scan, are an incredible and necessary resource. I have read the textbooks and attended the lectures, but I would not be where I am without FOAMed. I know all or most of those contributing to FOAMed do it out of love for education and patient care, without reimbursement or time off. Thank you to the many high-quality contributors and I am proud to play a small part in the FOAMed movement.schick_photo_5

Michael Schick, DO, MA, is Assistant Professor of Emergency Medicine at UC Davis Medical Center and Co-Director of Technology Enabled Active Learning, UC Davis School of Medicine. He is creator of www.sonostuff.com and can be reached on Twitter: ultrasoundstuff.

Handle the Scan with Care

Anytime one begins an obstetrical scan, there is a ritual that precedes our privileged access into an otherwise inaccessible place pulsating with life, hope and promise. The trilogy of preparing the patient, applying the gel, and selecting the transducer helps us transition as we open a window to the womb, sharing a highly anticipated and treasured moment with the family.

old windowWhile this privileged access may provide priceless reassurance, it is accompanied by a huge responsibility for the sonologist who is attempting to make sense of what is seen while trying to decide how to share the information with the family.

As diagnosticians, we are taught to be vigilant, careful and meticulous, making note of every single finding. We employ the most sophisticated machines and the importance of being non-paternalistic is deeply engrained in our brains. Yet at the same time, care and caring must come into play if we need to break news that may shatter dreams or induce significant parental anxiety.

Personally I find that the most challenging cases are those in which various isolated sonographic markers may be detected. The struggle between wanting to be scientific, factual and transparent and the fear of labeling an otherwise healthy being and worrying a hopeful parent becomes paramount. This is becoming more commonplace nowadays with the advancing technology as we delve into fetal evaluations with much more detail and at earlier points in gestation. We must not mistake normal developmental findings with pathology. We must be careful with enhanced image resolution and the employment of harmonics as these may increase tissue echogenicity and lead to over diagnosis of physiologic “cysts” in fluid producing structures.

With the continuing advancement of the technological capabilities of this most versatile of medical diagnostic modalities and its evolving portability, the number of probe-handlers globally is increasing exponentially across the disciplines. The problem is that education, training and experience are not uniform. The expertise to discuss the implications of various sonographic findings, particularly soft markers, and to recognize serious abnormalities, may be lacking. Despite the well-established positive impact of prenatal diagnosis, allowing us to prepare families and formulate the optimal plan of care, it may also be a double-edged sword, particularly in inexperienced hands.  As such, and in keeping with the mission of the AIUM and its communities of practice, the importance of proper training cannot be overstated. One must adhere to the basic sonographic teachings, employ the ALARA principle, and implement practice parameters when incorporating sonography into daily clinical practice. Referral to centers of excellence, whenever there may be doubt, is critical. Sound judgment remains the key to utilizing ultrasound first.

A new life is purity in the absolute form: a blank sheet of paper. Much caution must be exercised before any marks are made. Every word uttered has the potential of tainting the page, of taking away hope, of falsely “labeling” this promising life before it has even come into physical being. “First do no harm” should continue to echo in our brains and we must always proceed with caution, and tread with care.

What’s your opinion on the quality issue? Do you see a wide range of quality in ultrasound scanning?  Comment below or let us know on Twitter: @AIUM_Ultrasound.

Reem S. Abu-Rustum, MD, FACOG, FACS, FAIUM, is the Director of the Center For Advanced Fetal Care in Tripoli, Lebanon. She has served the AIUM in several capacities, including her current role on the AIUM Board of Governors.

  • Image adapted from A Practical Guide to 3D Ultrasound. RS Abu-Rustum. CRC Press 2015.

At the Intersection of Science, Engineering and Medicine

Flemming Forsberg PhDDuring the 2015 AIUM Annual Convention, AIUM sat down with Flemming Forsberg, PhD, recipient of the Joseph H. Holmes Basic Science Pioneer Award to talk about the award, his motivation, and the future of medical ultrasound. Here is what he had to say:

Question #1:
What was your reaction to being named the recipient of this award?

Question #2:
What motivates you?

Question #3:
What role does failure play?

Question #4:
How does the United States differ from the rest of the world when it comes to medical ultrasound?

Question #5:
Where do you see the future of medical ultrasound?


What do you see as the future of medical ultrasound? Where are there some additional intersections?
Comment below or let us know on Twitter: @AIUM_Ultrasound.

Flemming Forsberg, PhD, FAIUM, FAIMBE, received the 2015 Joseph H. Holmes Basic Science Pioneer Award from the AIUM. Dr Forsberg is Professor, Department of Radiology at Thomas Jefferson University. He also serves as Deputy Editor of the Journal of Ultrasound in Medicine.

The Issue with Keepsake Ultrasounds

Every cousmiling 3rd triple of weeks, the AIUM office receives a call from a reporter asking about keepsake (or entertainment) ultrasounds. Most of these calls result from a keepsake ultrasound facility opening in the community. A number of them came when the FDA reaffirmed its warning against the practice. Occasionally we get the oddball like the one about the ultrasound booth at a flea market.

Regardless of why the AIUM receives the call or inquiry, our response is the same. Since 1999, the AIUM has had the following official position:

“The AIUM advocates the responsible use of diagnostic ultrasound and strongly discourages the non-medical use of ultrasound for entertainment purposes. The use of ultrasound without a medical indication to view the fetus, obtain images of the fetus, or determine the fetal gender is inappropriate and contrary to responsible medical practice. Ultrasound should be used by qualified health professionals to provide medical benefit to the patient.”

AIUM, and a number of other professional associations in the U.S. and other countries, discourage the entertainment use of ultrasound for several reasons, including:

  1. The lack of training of the individuals obtaining the images. When it comes to keepsake ultrasound facilities, there are no regulations governing training requirements for those obtaining the images, either through certification or accreditation.
  2. The concern about potential biological effects that could result from scanning for a prolonged period, inappropriate use of color or pulsed Doppler ultrasound without a medical indication, or excessive thermal or mechanical index settings. As stated in the FDA’s position, “ultrasound can heat tissues slightly, and in some cases, it can also produce very small bubbles (cavitation) in some tissues.”
  3. The potential that pregnant women will visit a keepsake ultrasound facility in lieu of routine prenatal appointments with their medical doctor.

Despite government and medical association warnings against the use of keepsake ultrasounds, the number of facilities performing these scans appears to be increasing. Many theorize that this increase has been driven by the use of 3D ultrasound technology which provides detailed, in-depth images of the fetus and its appeal to expecting parents.

As the number of facilities increases, some states have taken action to ban the practice of keepsake ultrasounds based on the reasons outlined above. In 2009 Connecticut became the first state to ban keepsake ultrasounds. It took 5 years for the second state to take a similar action. Oregon’s law took effect in January of 2014.

Although the issue of keepsake ultrasounds has been around for decades, the recent proliferation of facilities offering this service has prompted action by medical organizations, the federal government, and state governments. Only time will determine the ultimate fate of keepsake ultrasound practices. Until then, the AIUM will continue to advocate for the responsible use of medical ultrasound.

What’s your take on keepsake/entertainment ultrasounds? Comment below or let us know on Twitter: @AIUM_Ultrasound.