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Medical ‘Miracles on 34th Street’

Brain Remaps Itself in Child with Double Hand Transplant

The first child to undergo a successful hand transplant is also the first child in whom scientists have detected massive changes in how sensations from the hands are represented in the brain. The brain reorganization is thought to have begun six years before the transplant, when the child had both hands amputated because of a severe infection during infancy. After he received transplanted hands, his brain reverted toward a more typical pattern.

Each area of the body that receives nerve sensations sends signals to a corresponding site in the brain. The spatial pattern in which those signals activate the brain’s neurons is called somatosensory representation—particular parts of the brain reflect specific parts of the body.

“We know from research in nonhuman primates and from brain imaging studies in adult patients that, following amputation, the brain remaps itself when it no longer receives input from the hands,” said first author William Gaetz, a radiology researcher in the Biomagnetic Imaging Laboratory at Children’s Hospital of Philadelphia (CHOP). “The brain area representing sensations from the lips shifts as much as two centimeters to the area formerly representing the hands.”

This brain remapping that occurs after upper limb amputation is called massive cortical reorganization (MCR). “We had hoped to see MCR in our patient, and indeed, we were the first to observe MCR in a child,” said Dr. Gaetz. “We were even more excited to observe what happened next—when the patient’s new hands started to recover function. For our patient, we found that the process is reversible.” 

Researchers from CHOP and the Perelman School of Medicine at the University of Pennsylvania published their findings in the Annals of Clinical and Translational Neurology. Their case report described Zion Harvey, now 10 years old, who received worldwide media coverage two years ago as the first child to undergo a successful hand transplant (Almanac December 15, 2015).

A 40-member team led by L. Scott Levin, chairman of orthopaedic surgery and a professor of plastic surgery at Penn Medicine, and director of the Hand Transplantation Program at CHOP, performed that milestone surgery in July, 2015 at CHOP. “Zion has been a child of many firsts here at Penn Medicine and Children’s Hospital of Philadelphia, and across the world,” said Dr. Levin, senior author of the paper. He added, “With the changes observed in his brain, which our collaborative team has been closely evaluating since his transplant two years ago, Zion is now the first child to exhibit brain mapping reorientation. This is a tremendous milestone not only for our team and our research, but for Zion himself. It is yet another marker of his amazing progress, and continued advancement with his new limbs.”

The researchers used magnetoencephalography (MEG), which measures magnetic activity in the brain, to detect the location, signal strength and timing of the patient’s responses to sensory stimuli applied lightly to his lips and fingers. They performed MEG four times in the year following the bilateral hand transplant, performing similar tests on five healthy children who served as age-matched controls.

At the first two visits, Zion’s fingertips did not respond to tactile stimulation—being touched with a thin filament. When experimenters touched the patient’s lips, the MEG signal registered in the hand area of the brain’s cortex, but with a delay of 20 milliseconds compared to controls. At the two later visits, MEG signals from lip stimulation had returned to the lip region of the brain, with a normal response time—an indication that brain remapping was reverting to a more normal pattern.

When experimenters touched Zion’s fingertips in the two later visits, the MEG signals appeared in the hand region of the brain, with a shorter delay in response time from visit 3 to visit 4, but with higher-than-normal signal strength. “The sensory signals are arriving in the correct location in the brain, but may not yet be getting fully integrated into the somatosensory network,” said Dr. Gaetz. “We expect that over time, these sensory responses will become more age-typical.”

Dr. Gaetz added, “These results have raised many new questions and generated excitement about brain plasticity, particularly in children. Some of those new questions include, what is the best age to get a hand transplant? Does MCR always occur after amputation? How does brain mapping look in people born without hands? Would we see MCR reverse in an adult, as we did in this patient? We are planning new research to investigate some of these questions.”

Zion’s progress provides encouraging details on his functional abilities. “Our follow-up studies 18 months after this transplant showed that he is able to write, dress and feed himself more independently than before his operation—important considerations in improving his quality of life,” said Dr. Levin.

 

A Transplant and a Cure: Penn Team Eradicates Hepatitis C in 10 Patients Following Lifesaving Transplants from Infected Donors

Ten patients at Penn Medicine have been cured of the Hepatitis C virus (HCV) following lifesaving kidney transplants from deceased donors who were infected with the disease. The findings point to new strategies for increasing the supply of organs for the nation’s more than 97,000 patients who are awaiting kidney transplants—often for as many as five or more years.

In 2016, Penn Medicine launched an innovative clinical trial to test the effect of transplanting kidneys from donors with HCV into patients currently on the kidney transplant waitlist who do not have the virus, and who opt in to receive these otherwise unused organs. Recipients were then treated with an antiviral therapy in an effort to cure the virus. Early data from the study were presented by David S. Goldberg, an assistant professor of medicine and epidemiology in the Perelman School of Medicine at Penn, at the 2017 American Transplant Congress in Chicago, and were simultaneously published in the New England Journal of Medicine.  

“We started this trial in the hopes that, if successful, we could open up an entirely new pool of donor organs, and effectively transplant hundreds, if not thousands, more patients who are awaiting a lifesaving organ,” Dr. Goldberg said. “Historically, Hepatitis C-infected kidneys were often discarded, and were thought to be damaged or too ‘high-risk.’ Our pilot data demonstrate the ability to cure the contracted virus following transplantation in this patient population. If future studies are successful, this may be a viable option for patients who may otherwise never see a transplant.”

Dr. Goldberg, who co-led the study with Peter Reese, an assistant professor of medicine and epidemiology at Penn Medicine and chair of the Ethics Committee for the United Network of Organ Sharing (UNOS), approached and enrolled participants who relied on dialysis treatments to stand in for their damaged kidneys. Participants were between 40 and 65 years of age and had been waiting for a transplant for at least a year and a half. A three-step process of education and consent was used during pre-enrollment to ensure patients, and their loved ones were provided with a comprehensive understanding of the risks. Once enrolled, and as organs became available, the team performed HCV donor genotyping during the allocation process, selecting only kidneys that were considered “high quality.”

In the first phase of the study, to date, 10 patients have received transplants using the protocol. On average, patients received a transplant 58 days after enrolling in the trial—some in as quickly as 11 days, while others waited for more than 100 days. At three days after surgery, patients were tested for HCV, and all 10 tested positive for the disease. Next, the participants were treated with the standard 12-week course of elbasvir/grazoprevir, commonly known as Zepatier, a recently-approved and highly effective oral medication prescribed to eradicate HCV. All 10 patients have been cured of their contracted HCV.

“For so long, HCV was a virus with a very negative stigma associated with it, especially among physicians. So it was interesting to see that patients were quick to jump at the chance to get this transplant, despite the possibility that they could get Hepatitis C permanently,” Dr. Reese said. “Going into the study, we knew it was a possibility that some or all of the patients would contract HCV, and that they could have the disease for the rest of their lives if we were unsuccessful. But for these patients, getting off of dialysis and getting back to their normal lives was very much worth the risk.”

Following the early positive results, the research team was granted an extension of their study, which will allow them to transplant and treat an additional 10 patients—20 patients in total.

The research team is designing a new clinical trial that will study this same approach in patients who are heart-transplant recipients, and in the future they hope to examine the efficacy of this approach in liver and lung transplants. Researchers note there is a need for longer and larger trials to continue evaluating the effectiveness of HCV-positive to HCV-negative transplantation followed by antiviral therapy in a broader population.

Additional Penn Medicine experts involved in this study span disciplines including infectious diseases, transplantation surgery, gastroenterology, hepatology, and pathology and laboratory medicine, including Deirdre Sawinski, Roy Bloom, Raj Reddy, Emily Blumberg, Jennifer Trofe-Clark, Vivianna Van Deerlin, Midhat Farooqi, Peter Abt, Matthew Levine, Paige Porrett, Susanna Nazarian, Ali Naji, Maureen McCauley and Anna Sicilia. The study is supported by a research grant from the Merck Investigator Initiated Studies Program, and Merck supplied the antiviral drugs used in the study.

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