Author Insights: Bone Marrow Transplant an Emerging Option for Adults With Sickle Cell Disease

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and colleagues found a less toxic bone marrow transplant strategy was effective for adults with sickle cell disease. Image: NIH

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and colleagues found a less toxic bone marrow transplant strategy was effective for adults with sickle cell disease. Image: NIH

Although children with sickle cell disease have benefited from the emergence of improved therapies, options for adults with the disorder have lagged and many die in their early 40s. New evidence published today in JAMA suggests that a less toxic bone marrow transplant technique may provide adults with a new option.

Sickle cell disease is caused by a genetic variation that results in the production of sickle-shaped blood cells. These cells can clump together, causing blockages in blood vessels, severe pain, and even stroke. Over time, damage to multiple organs can occur. Blood transfusions, prophylactic antibiotic therapies, and other interventions help manage patients’ symptoms, but only bone marrow transplantation can cure the disease. Although about 400 children have received such transplants to date, adults are less able to tolerate this potentially curative treatment, which involves completely destroying the patient’s own bone marrow and replacing it with marrow cells from a compatible donor.

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and his colleagues found that a less drastic technique for bone marrow transplantation may be a better option for adults. Instead of using radiation to completely eliminate the patient’s own bone marrow before transplant, Tisdale and colleagues reduced the patient’s bone marrow by half. After transplant, the patient has bone marrow containing a mix of his or her own marrow cells and the donor’s marrow cells.

The researchers tested their technique in 30 patients aged 16 years to 65 years. One patient died after a relapse to sickle cell, but 29 survived for an average of 3.4 years without relapse. In 26 patients, the donor cells engrafted without an autoimmune reaction, and 15 were able to discontinue immunosuppressive treatment. Treated patients also required fewer sickle cell–related hospitalizations.

Tisdale discussed the findings with news@JAMA.

news@JAMA: Why did you decide to do the study?

Dr Tisdale: Adults with sickle cell disease not only have a difficult life, with pain and organ damage, but they die early. Despite progress in supportive care, the median age at death for patients with sickle cell remains the early 40s. That hasn’t changed in decades.

news@JAMA: Why hasn’t bone marrow transplantation been as successful for adults as it has for children?

Dr Tisdale: Bone marrow transplant, like most medical therapy, is easier for children to undergo. They tolerate chemotherapy, radiation, and bone marrow transplants better because they have more reserve. Adults tolerate it less well. The older you are the worse you’ll do with a transplant.

news@JAMA: Why don’t all children with sickle cell disease receive bone marrow transplants?

Dr Tisdale: The first bone marrow transplant was in a kid with sickle cell and leukemia. The child had a life-threatening illness and the only cure was bone marrow transplantation. The child was cured of the leukemia and sickle cell. It was next tried in kids with sickle cell who’d had a stroke.

It’s generally reserved for children with sickle cell who have some indication they are not doing well. Children do pretty well with sickle cell, so you don’t want to do something as harsh as a bone marrow transplant to a child who is doing well. There is also some resistance from families because high doses of radiation render the children sterile. Some think it’s better to wait until these children are adults and let them decide.

news@JAMA: How is your approach different?

Dr Tisdale: We tried to make bone marrow transplant safer so it wasn’t such a big trade-off for adults. It’s different in 2 fundamental ways. It doesn’t completely destroy the marrow. In a standard transplant, if the transplant doesn’t “take,” the patient dies because they can’t recover bone marrow. If our strategy doesn’t work, the patient’s own bone marrow comes back and they go back to having sickle cell. We also were striving for [immune] tolerance between donor and recipient.

news@JAMA: What are the next questions you need to answer?

Dr Tisdale: Our next big question is, can we extend this to more patients by loosening the criteria for the donor? What if it required a half match rather than full match? Most patients don’t have a full-match sibling. But virtually everyone has a half match—parents, sibling, or child.

news@JAMA: What’s the main take-home message?

Dr Tisdale: Adult patients with sickle cell and their care providers should consider whether a transplant is an option.

Author Insights: After a Year of Planning, Initiative to Probe the Brain Moving Forward

For its part in the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the National Institutes of Health is initially focused on accelerating technology development to improve brain research. (Image: NIH)

For its part in the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the National Institutes of Health is initially focused on accelerating technology development to improve brain research. (Image: NIH)

A major federally funded project designed to unlock the mysteries of the brain is under way and, after a year of planning, the initiative’s focus has begun to sharpen. A Viewpoint appearing today online in JAMA Neurology explains the intent of the project, the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which one day may give scientists and physicians insights to treat or prevent disease or illness stemming from brain malfunction.

The BRAIN Initiative, launched April 2, 2013, is a partnership with the National Institutes of Health (NIH), the National Science Foundation, the Defense Advanced Research Projects Agency, private foundations, and researchers. For fiscal year 2014, President Obama called for a total of $110 million to support the BRAIN Initiative. The NIH will receive $40 million and focus on several areas of research, such as generating a census of brain cell types, creating structural maps of the brain, and linking neuronal activity to behavior.

Coauthor of the Viewpoint, Cornelia I. Bargmann, PhD, an investigator with the Howard Hughes Medical Institute, The Rockefeller University, New York City, talked with news@JAMA about the BRIAN Initiative.

news@JAMA: Why study the brain?

Dr Bargmann: The goal of the initiative is to understand how the brain functions as an organized unit, to develop a foundation of knowledge that will ultimately allow us to understand which circuits go wrong for different disorders, or how different kinds of defects spread from one initial insult to the brain. We want to really understand the brain as a whole and not just individual pieces.

news@JAMA: Why is this important?

Dr Bargmann: Some kinds of dysfunction of the brain, such as autism, schizophrenia, depression, Alzheimer disease, traumatic brain injury, or post-traumatic stress disorder, will affect 1 in 3 American at some point of their lives. Although they have different causes, they are fundamentally associated with defects in brain function.

news@JAMA: When can we expect results that directly improve an individual’s health?

Dr Bargmann: It’s important to not raise false hopes and make empty promises. The BRAIN Initiative is intended to stimulate technology development and put tools in the hands of scientists and physician scientists to make discoveries that can lead to the treatment or prevention of diseases such as Alzheimer disease.

It’s the first step in building the foundational knowledge. Look at cancer treatment in the past few decades. We can see where science in the 1980s led to new therapies only approved in the late 1990s, such as Gleevec, and only now is it leading to a large armamentarium of anticancer treatments.

news@JAMA: What do you say to those who, when the BRAIN Initiative was announced, were saying the project lacked focus with no defined goals.

Dr Bargmann: When the Brain Initiative was first announced, it was pretty vague. But the NIH developed a year-long planning process to make the Brain Initiative more concrete. It’s trying to look at all the areas that contribute to our understanding of the working of the brain. The planning process hopefully identified what’s achievable, what’s ambitious, and what’s fantastical.

news@JAMA: Reading your Viewpoint, it seems you fully support the BRAIN Initiative.

Dr Bargmann: Everyone should be excited about the BRAIN Initiative. I’m a neuroscientist, and I think knowing how the brain works is the coolest thing we can know.

Stroke Risk Increased After Shingles Infection

Risk of stroke is increased in the 6-month period following shingles infection. Image: ©iStock.com/RosicaSabotanova

Risk of stroke is increased in the 6-month period following shingles infection. Image: RosicaSabotanova/iStock.com

New evidence suggests that shingles, which can occur in individuals who previously had chicken pox, may be associated with an increased risk of stroke in the weeks to months following a shingles episode.

Shingles, or herpes zoster, which is the result of the same virus (varicella zoster virus) that causes chicken pox, affects 1 million Americans every year. Before a vaccine for shingles became available, one-third of Americans were affected with shingles in their lifetime. Shingles occurs when the dormant virus reactivates in someone who had chicken pox in the past.

The infection targets the nervous system, and can have both short-term and long-term health effects, including the hallmark painful shingles rash that may be followed by persistent nerve-related pain that can last for months to years after the rash resolves. Now, new evidence suggests that the shingles may also be associated with an increased risk of stroke in the weeks after the rash emerges.

In a study released yesterday in Clinical Infectious Diseases, researchers at the London School of Hygiene and Tropical Medicine analyzed medical records from millions of general practice patients in the United Kingdom from 1987 to 2012 and identified more than 6500 individuals with both shingles and arterial stroke during this period. When they looked at the time points at which strokes occurred in relation to the shingles episodes, they found that the rate of stroke was significantly higher during the first 6 months following a shingles episode compared with before a shingles episode (approximately 63% higher during the first month, 42% higher during the second and third months, and 23% higher during the fourth through sixth months.)

Individuals who did not receive antiviral treatment during their shingles episodes had an even higher rate of stroke compared with those who did receive such treatment. In addition, though the case numbers were smaller, individuals in whom shingles affected the trigeminal nerve, a cranial nerve that affects facial sensation, seemed to have a higher rate of stroke than those in whom other nerves were affected.

The authors suggest 2 possible mechanisms in which shingles might increase stroke risk. First, the overall higher level of inflammation in the body during a severe systemic infection causes a state in which the blood is more prone to clotting, which can lead to stroke. Second, the shingles virus can also spread into the nerves of the blood vessel walls, leading to defective blood vessels that are more likely to allow both clots and bleeding, which can lead to stroke.

This study is the first to examine the association between shingles and stroke in a time-dependent fashion, including only individuals with both shingles and stroke, and focusing on the length of time between the 2 events. Previous studies comparing the rates of stroke in individuals who had shingles with those who did not have also found higher stroke risks in persons with prior shingles, but because the characteristics of people who get shingles and those who do not may be very different, many other confounding factors could have affected the results. This approach, on the other hand, allowed patients to serve as their own controls (with the control periods being when they were outside of a 1-year period from infection), which, according to the authors, makes the association more robust.

The authors state that their findings have implications for both clinical medicine and public health, underscoring the importance of antiviral treatment for shingles as well as shingles vaccination, which, in the United States at least, remains underused.

Author Insights: Neuroimaging for Headache is Overused and Provides Little Additional Benefit

Brian C. Callaghan, MD, MS, an assistant professor of neurology at the University of Michigan Health System in Ann Arbor, and colleagues suggest headache neuroimaging is common, costly, and overused. (Image: University of Michigan)

Brian C. Callaghan, MD, MS, an assistant professor of neurology at the University of Michigan Health System in Ann Arbor, and colleagues suggest headache neuroimaging is common, costly, and overused. (Image: University of Michigan)

Although most headaches are caused by benign conditions, sometimes they signal the presence of a more dangerous condition, such as a brain tumor or aneurysm. To determine if such a condition is present, a physician, often at the request of the patient, will order neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI).

But a research letter appearing Monday in JAMA Internal Medicine suggests neuroimaging for headache generally goes against current recommendations from multiple guidelines; is overused, costing the health system hundreds of millions of dollars; increases patient radiation exposure; and can detect incidental findings that lead to other tests and procedures for often benign conditions.

Using the National Ambulatory Medical Care Survey, the study authors found that from 2007 through 2010, there were 51.1 million adult headache visits, mostly to primary care physicians (54.8%); 88% were by patients younger than 65 years and 78% were by female patients. Neuroimaging occurred for 12.4% of all headache visits during that period, costing a total of $3.9 billion, and the use of neuroimaging for headaches has increased substantially in recent years, from 5.1% in 1995 to 14.7% in 2010.

Lead author Brian C. Callaghan, MD, MS, an assistant professor of neurology at the University of Michigan Health System in Ann Arbor, discusses his team’s findings.

news@JAMA: Why has the use of neuroimaging for routine headaches increased in recent years?

Dr Callaghan: My speculation is that imaging use in general has been increasing across the board as MRI and CT become more accessible. But the number one reason physicians give scans for headache is patient reassurance, not to detect a bad intracranial condition. The next reason is legal—physicians not willing to miss the very rare condition.

news@JAMA: Do reassurance and concerns about potential legal consequences have societal costs?

Dr Callaghan: The major problem is that we’re ordering lots of tests, and it’s a huge amount of money. Headache neuroimaging is one of the big-ticket items where we spend a lot of money, and we don’t get much bang for our buck.

news@JAMA: Why do patients seek reassurance, and is there a cost to seeking such reassurance?

Dr Callaghan: If you ask most patients who have had bad headaches why they want a scan, they would say that they worry about a brain tumor. But they don’t think about the other things that can harm them. They don’t appreciate some of the downstream consequences, like radiation exposure from CT or undergoing an MRI scan and getting a false-positive for something else that leads to more tests and procedures.

news@JAMA: How should physicians reassure patients who request imaging because they worry their headaches signal a serious condition?

Dr Callaghan: There are some circumstances where neuroimaging is warranted, but if the physician feels this is not one of those circumstances, he or she has to have a conversation with the patient to explain why the headaches are occurring and why an imaging test, with its potential side effects, is not warranted.

Poliolike Cases in California Under Investigations, But Appear Unlikely to Pose Public Health Threat

Unusual cases of poliolike illnesses in California have created a buzz, but experts and public health officials say they do not pose a public health threat. Image: Tagxedo

Unusual cases of poliolike illnesses in California have created a buzz, but experts and public health officials say they do not pose a public health threat. Image: Tagxedo

News about a poliolike illness detected in California has created quite a stir in the news media, but there is some disagreement about how concerning these rare cases are.

In the autumn of 2012, Keith Van Haren, MD, a pediatric neurologist at the Lucile Packard Children’s Hospital at Stanford University in California, and other neurologists across the state noticed an unusual trend: the emergence of several cases of sudden-onset paralysis in children who also had motor neuron injury. He and his colleagues normally can expect to see 1 such case a year, he said. But as he and his colleagues describe in an abstract released in February that will be presented at the American Academy of Neurology’s annual meeting in late April, 5 such cases were reported within a period of 18 months, including 2 that tested positive for human enterovirus 68. This virus has been linked to clusters of respiratory illness, and at least 1 case involving neurological symptoms had previously been reported. According to Van Haren, a total of 20 such cases have been detected in California in the past 18 months.

“The physician community is taking this very seriously, and is invested in figuring out the cause,” Van Haren cautioned. “But it remains rare.”

Benjamin Haynes, a Centers for Disease Control and Prevention (CDC) spokesperson, said the agency is closely monitoring the situation and has consulted with officials from the California Department of Public Health. But so far, it does not appear that the number of cases rise above the background rates of sudden-onset paralysis that would be expected in California in a given year, Haynes said. Acute flaccid paralysis can have a number of causes, including tick paralysis, Guillain-Barré syndrome, and botulism. However, it is not a condition physicians are required to report to the CDC, so the data are limited.

“At this time, CDC does not think the situation in California poses a public health threat, but we encourage parents to speak with their doctors or pediatricians if they have concerns,” Haynes said.

But Van Haren, who is accustomed to seeing patients with more typical presentations of acute paralysis, said he and his colleagues believe these cases are occuring more frequently than the baseline rate, and noted that there are no data on this particular subset of patients. Additionally, he said these patients are presenting with more severe disability and experiencing less recovery than would be expected with most cases of acute flaccid paralysis.

The California Department of Health has not found any common cause among the cases, but will continue to investigate, according to a statement from Gil Chavez, MD, MPH, Deputy Director of the Center for Infectious Disease and State Epidemiologist.

More Calories, Carbs May Slow Progression of Lou Gehrig Disease

New research indicates that a high-calorie, high-carbohydrate diet may delay disease progression in patients with the neurodegenerative disease amyotrophic lateral sclerosis. (Image: Sean_Gao/iStockphoto.com)

New research indicates that a high-calorie, high-carbohydrate diet may delay disease progression in patients with the neurodegenerative disease amyotrophic lateral sclerosis. (Image: Sean_Gao/iStockphoto.com)

Results from a small study suggest that a high-calorie, high-carbohydrate diet may be a safe, simple treatment for amyotrophic lateral sclerosis (ALS), a progressive neurological disorder commonly known as Lou Gehrig disease.

Amyotrophic lateral sclerosis destroys nerve cells in the brain, leading to weakness, paralysis, and often death from respiratory failure. Because patients with the disease experience muscle atrophy and find it physically difficult to consume enough calories to maintain weight, they usually have substantial weight loss.

However, previous studies have shown that moderately obese patients with ALS lived longer and their disease progressed more slowly than underweight patients. Studies in a mouse model of ALS also linked a calorie-dense, high-fat diet with weight gain and delayed disease progression.

Reporting online in The Lancet, a team of US researchers randomly assigned 20 patients with advanced ALS to 1 of 3 diet groups: a weight maintenance group, a high-calorie, high-fat group, or a high-calorie, high-carbohydrate group. The patients already were receiving nutrition through feeding tubes and, on average, had lost about 20% of their body weight.

After 4 months on their assigned diet, patients were followed-up for 5 months primarily to evaluate the diets’ safety and tolerability. Those on the high-calorie, high-carbohydrate diet had the fewest adverse events: 23 adverse events among 8 patients compared with 42 among 6 patients in the weight maintenance group and 48 adverse events among 6 patients in the high-calorie, high-fat group. Gastrointestinal complications were the most common adverse events, and they occurred least often with the high-calorie, high-carbohydrate diet and most often with the high-calorie, high-fat diet.

Patients in the high-calorie, high-carbohydrate group gained about 1 pound per month, the weight maintenance group gained about one-quarter of a pound monthly, and the high-calorie, high-fat group lost about 1 pound per month even though their diet provided about 150% of the calories needed to keep their weight steady. Complications from weight gain, such as diabetes or heart disease, did not occur.

Four patients died during the first 4 months of the study—3 in the weight maintenance group and 1 in the high-calorie, high-fat group. The investigators reported that respiratory failure caused all the deaths and that mortality wasn’t related to the study diet. No deaths were reported in the high-calorie, high-carbohydrate group.

“This pilot study demonstrates the safety of a novel, simple, low-cost treatment for a devastating disease where currently, very few treatment options are available,” lead author Anne-Marie Wills, MD, of Massachusetts General Hospital in Boston, said in a statement. The sole drug approved by the US Food and Drug Association for patients with ALS is riluzole, which provides only a small survival benefit.

“The survival component of this study is the crucial issue,” Ammar Al-Chalabi, MD, PhD, of King’s College in London, England, wrote in an accompanying editorial. He noted that the ease and apparent safety of changing to a high-calorie, high-carbohydrate diet “might be regarded as sufficient evidence to change to such a diet.” However, Al-Chalabi also wrote that he won’t change practice with his own patients without results from larger studies.

Study: Constant Refrigeration Not Needed to Deliver Viable Meningitis Vaccine to Rural Africa

A new study found that a meningitis A vaccine can be delivered to remote areas in Africa and remain viable without the need for constant refrigeration. (Image: Rodrigue Barry/WHO-AFRO)

A new study found that a meningitis A vaccine can be delivered to remote areas in Africa and remain viable without the need for constant refrigeration. (Image: Rodrigue Barry/WHO-AFRO)

One of the reasons that millions of people worldwide are undervaccinated and susceptible to vaccine-preventable diseases is the need to keep vaccines refrigerated—something that is difficult to do in warm and hard-to-reach areas of the world.

But a 10-day pilot project to deliver meningitis A vaccine to a remote area of Benin in western Africa found it is possible to deliver efficacious vaccine without the need to maintain refrigeration. The project’s description and results were published online this week in Vaccine.

MenAfriVac is a meningitis A polysaccharide conjugate vaccine intended for use across the sub-Saharan African “meningitis belt,” countries in which the incidence of the infection is high. As with most vaccines, MenAfriVac was supposed to be kept at a temperature between 2°C and 8°C (36°F and 46°F). In October 2012, based on scientific studies and analyses submitted by the vaccine manufacturer (Serum Institute of India), MenAfriVac’s regulatory agency of record (India) and the World Health Organization (WHO) both approved a temperature control revision that said the vaccine could be stored at temperatures up to 40°C (104°F) for not more than 4 days immediately prior to administration.

Vaccine vials were transported in coolers without ice. To ensure that the vaccine did not exceed the 40°C threshold, the project coordinators placed inside each cooler a card inside that changes color immediately upon being exposed to 40°C. They also affixed to the vaccine label a vaccine vial monitor, a heat-sensitive sticker that changes color to reflect cumulative exposure to heat.

Armed with those safeguards, vaccination teams, each comprising a nurse and 2 volunteers, set off for 150 villages and hamlets in Banikoara, a rural area in northern Benin, with the goal of vaccinating an estimated 147 000 children and adults up to age 30 years. Ultimately, the vaccination teams immunized 155 596 children and adults, with each team vaccinating on average 318 individuals a day. Only 9 of about 15 000 vaccine vials were discarded for surpassing the 4-day limit, and no vial was discarded because it was exposed to a temperature of 40°C or higher or because a vaccine vial monitor had reached its end point.

“Finding solutions to reducing the cost and logistical challenges of reaching people living in remote areas would remove a major constraint to achieving universal coverage with vaccines beyond MenAfriVac. Indeed, a similar approach is being explored with the manufacturers of other vaccines, such as the yellow fever or the oral cholera vaccines,” commented Michel Zaffran, coordinator of WHO’s Expanded Program on Immunization and former director of Optimize, a WHOand PATH collaboration aimed at improving immunization systems and technologies, in a release.

Support for the operational costs of the campaign was provided by the Global Alliance for Vaccine and Immunization. Optimize, funded by the Bill & Melinda Gates Foundation, provided additional specific funds for training, supervision, and the evaluation of the project.