Brain Cooling May Prevent Epilepsy Induced by Trauma

A study in rats showing brain cooling after trauma may prevent seizures brought on by the trauma.

In the weeks, months and years after a severe head injury, patients often experience epileptic seizures that are difficult to control. A new study in rats suggests that gently cooling the brain after injury may prevent these seizures.

"Traumatic head injury is the leading cause of acquired epilepsy in young adults, and in many cases the seizures can't be controlled with medication," says senior author Matthew Smyth, MD, associate professor of neurological surgery and of pediatrics at Washington University School of Medicine in St. Louis. "If we can confirm cooling's effectiveness in human trials, this approach may give us a safe and relatively simple way to prevent epilepsy in these patients."

The researchers reported their findings in Annals of Neurology.

Cooling the brain to protect it from injury is not a new concept. Cooling slows down the metabolic activity of nerve cells, and scientists think this may make it easier for brain cells to survive the stresses of an injury.

Doctors currently cool infants whose brains may have had inadequate access to blood or oxygen during birth. They also cool some heart attack patients to reduce peripheral brain damage when the heart stops beating.

Smyth has been exploring the possibility of using cooling to prevent seizures or reduce their severity.

"Warmer brain cells seem to be more electrically active, and that may increase the likelihood of abnormal electrical discharges that can coalesce to form a seizure," Smyth says. "Cooling should have the opposite effect."

Smyth and colleagues at the University of Washington and the University of Minnesota test potential therapies in a rat model of brain injury. These rats develop chronic seizures weeks after the injury.

Researchers devised a headset that cools the rat brain. They were originally testing its ability to stop seizures when they noticed that cooling seemed to be not only stopping but also preventing seizures.

Scientists redesigned the study to focus on prevention. Under the new protocols, they put headsets on some of the rats that cooled their brains by less than 4 degrees Fahrenheit. Another group of rats wore headsets that did nothing. Scientists who were unaware of which rats they were observing monitored them for seizures during treatment and after the headsets were removed.

Rats that wore the inactive headset had progressively longer and more severe seizures weeks after the injury, but rats whose brains had been cooled only experienced a few very brief seizures as long as four months after injury.

Brain injury also tends to reduce cell activity at the site of the trauma, but the cooling headsets restored the normal activity levels of these cells.

The study is the first to reduce injury-related seizures without drugs, according to Smyth, who is director of the Pediatric Epilepsy Surgery program at St. Louis Children's Hospital.

"Our results show that the brain changes that cause this type of epilepsy happen in the days and weeks after injury, not at the moment of injury or when the symptoms of epilepsy begin," says Smyth. "If clinical trials confirm that cooling has similar effects in humans, it could change the way we treat patients with head injuries, and for the first time reduce the chance of developing epilepsy after brain injury."

Smyth and his colleagues have been testing cooling devices in humans in the operating room, and are planning a multi-institutional trial of an implanted focal brain cooling device to evaluate the efficacy of cooling on established seizures.

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FDA Panel Backs Brain Stimulator to Lower Rate of Seizures

A panel for the FDA has unanimously supported a brain stimulator that lowers the rate of seizures in people with epilepsy.

A U.S. Food and Drug Administration panel has unanimously backed a device that lowers the rate of seizures among people with epilepsy.

Smaller and thinner than an implantable defibrillator, the battery-powered, programmable device, called the RNS System, is placed just under the skull during surgery. Electrodes reach from the device to the one or two places in the patient's brain that create the abnormal electrical activity that causes seizures. The device works by short-circuiting nerve cells in that area to normalize brain activity before a seizure is triggered.

On Friday, the panel voted 11-0, with two members abstaining, to recommend approval of the system, according to MedPage Today. The FDA does not have to follow the recommendations of its expert panels, but it typically does.

"This is the first responsive neuro-stimulation system ever designed," said Frank Fischer, president and CEO of Mountain View Calif.-based NeuroPace Inc., which developed the device. "Our long-term results show that patients have a reduction of 50 percent or more in their seizure frequency, compared to baseline, and a lessening of seizure severity."

The device is designed specifically for people aged 18 and older with partial-onset epilepsy, which occurs when one or more fixed locations in a person's brain start the cascade of nerve firing that creates a seizure.

NeuroPace has done two studies involving a total of 256 patients who were monitored for a period of between two and nine years, without any significant problems, according to Fischer.

Epilepsy is a brain disorder in which a person suffers repeated seizures over time.

It affects more than 2 million Americans, according to the Epilepsy Foundation, making it the third most common neurological disorder in the United States, after Alzheimer's and stroke. Seizures are episodes of disturbed brain activity that cause changes in attention or behavior. Brain cells keep firing instead of acting in an organized way. The malfunctioning electrical system of the brain causes surges of energy that can cause a person to have muscle contractions or to black out.

Physicians can modify the programming of the device even after it has been implanted, to reflect a patient's needs over time, Fischer said. They can also observe the brain activity of a patient from a laptop computer in their office -- to help them manage a patient's treatment, he said.

Representatives of the Epilepsy Foundation said new treatments for epilepsy are sorely needed.

"We're not in a position to evaluate everything that an evaluating committee would be looking at, but we do advocate for access to treatments once they're FDA-approved," explained Angela Ostrom, vice president of public policy and advocacy for the Epilepsy Foundation, based in Landover, Md.

While Fischer said it is too soon to say what the device might cost, comparable systems for heart problems range in price from $30,000 to $35,000, not including the cost of the surgery to implant the device. The battery that powers the device lasts about three years. When it fails, a new device has to be substituted in a 30-to-60-minute outpatient surgical procedure, Fischer said.

Fischer said the company has spent 15 years developing the device.

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More about the Brain Stimulator Approved by FDA Panel

This article discusses more about the brain stimulator device that was unanimously approved by the FDA panel.

A neurological device under review by the FDA helped reduce the incidence of seizures while not greatly increasing side effects, the agency said Thursday.

The NeuroPace RNS System lowered the rate of seizures by 37.9% during a 3-month blinded evaluation period when turned on, compared with 17.3% when not turned on (P=0.012), briefing documents released ahead of an FDA advisory committee meeting showed.

"Following implant of the device and prior to initiation of stimulation, there is a reduction in seizure frequency in terms of mean or median," FDA reviewers said in the document.

The FDA's Neurological Devices Panel of the Medical Devices Advisory Committee will meet Friday to review the application of Mountain View, Calif.-based NeuroPace for approval of its RNS System for use as adjunct therapy to reduce the frequency of seizures in adults.

The RNS System is surgically implanted under the skin on the skull and records electrocorticographic (ECoG) patterns via electrodes. The device delivers short electrical pulses intended to interrupt the triggers in the brain that cause epileptic seizures.

Physicians can review ECoG recordings and assess the relationship between the device's detections and reported clinical seizures, and then adjust the RNS System's electrical pulses accordingly.

The device was studied in a randomized, double-blinded, sham-controlled trial of 191 people. Patients were required to remain on a stable anti-epileptic drug regimen; patients included in the trial had had three or more disabling seizures per month for 3 consecutive months. Roughly half the patients were randomized to have the RNS System turned on, while it remained off in the other half during a 3-month study period.

While most patients appeared to benefit from the device, there were some even in the treatment arm who worsened. "There were four subjects in the treatment group and 10 subjects in the sham group who experienced a greater than 50% increase in seizures during the blinded-evaluation period," the FDA said.

NeuroPace said 53% of patients implanted with its device experienced a 50% drop in the number of seizures 2 years after implantation.

The company also conducted a post-hoc, month-by-month analysis and found that by the end of the third month, patients with the device turned on experienced a 41.5% decrease in seizure frequency, compared with 9.4% of those who had the device off.

The FDA noted that the analysis excludes two outlying patients from the sham arm. When included in that post-hoc analysis, the efficacy difference was 40.1% versus 22.9% for the treatment and sham groups, respectively, the agency found.

The agency found that the number of adverse events -- mild and serious -- didn't differ significantly between the two trial arms. Serious adverse events (SAEs), including brain hemorrhaging and implantation-site infections, occurred in 4.2% of treatment patients and 5.4% of sham patients during the blinded evaluation period.

"Although comparable to the incidence of SAEs with other invasive intracranial procedures ... the majority of these SAEs would not be expected to occur in a comparable medically treated population with intractable epilepsy," the FDA said.

The FDA noted nine deaths in all the trials, including six from epilepsy. There were also 14 intracranial hemorrhages.

NeuroPace initially filed a marketing application with the FDA for the RNS System in July 2010, but the agency requested 12-month follow-up data on all patients in the trial. The FDA also sent a Major Deficiency Letter in June 2011 seeking clarification on statistical and clinical issues.

Although there are many approved medications for epileptic seizures, they cause significant adverse events when used in combination, the FDA said this week.

"These adverse effects can be especially problematic in vulnerable populations such as young patients still in school, those with jobs requiring cognitive skills, those operating dangerous equipment, or the elderly already on multiple drugs," the agency said.

The FDA is not required to follow the opinion of its advisory committees but usually does.

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Childrens' sleep reinforces what they learn during the day

Studies show that the brain stores knowledge learned during the day during sleep. This is true for both adults and children, but it is more effective in children.

During sleep, our brains store what we have learned during the day ‒ a process even more effective in children than in adults, new research shows.

It is important for children to get enough sleep. Children's brains transform subconsciously learned material into active knowledge while they sleep -- even more effectively than adult brains do, according to a study by Dr. Ines Wilhelm of the University of Tübingen's Institute for Medical Psychology and Behavioral Neurobiology. Dr Wilhelm and her Swiss and German colleagues have published their results in Nature Neuroscience.

Studies of adults have shown that sleeping after learning supports the long-term storage of the material learned, says Dr Wilhelm. During sleep, memory is turned into a form that makes future learning easier; implicit knowledge becomes explicit and therefore becomes more easily transferred to other areas.

Children sleep longer and deeper, and they must take on enormous amounts of information every day. In the current study, the researchers examined the ability to form explicit knowledge via an implicitly-learned motor task. Children between 8 and 11, and young adults, learned to guess the predetermined series of actions -- without being aware of the existence of the series itself. Following a night of sleep or a day awake, the subjects' memories were tested. The result: after a night's sleep, both age groups could remember a larger number of elements from the row of numbers than those who had remained awake in the interim. And the children were much better at it than the adults.

"In children, much more efficient explicit knowledge is generated during sleep from a previously learned implicit task, says Wilhelm. And the children's extraordinary ability is linked with the large amount of deep sleep they get at night. "The formation of explicit knowledge appears to be a very specific ability of childhood sleep, since children typically benefit as much or less than adults from sleep when it comes to other types of memory tasks."

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Childhood Epilepsy, Memory, and Health Quality - No Connection to Seizure Frequency

Children with epilepsy and poor memory, in this study,  appear to have lower health-related quality of life.

Interestingly, this finding is not connected to seizure frequency.

As an illness, there is an experience that is broader than just the "seizures". 

Ask your neurologist about cognitive, attention, and emotional problems. Assess your child's sleep. Assess the effects of medications. Bone health, nutrition, weight gain and loss are all common problems. - JR

Poor memory in children with epilepsy linked to lower health related quality of life

(dailyRx News) Memory is often an area of concern for people with epilepsy. For children who are just learningabout the world around them, memory can be of particular importance to their physical, mental, emotional and social development.

A recent study investigated the link between memory and health-related quality of life - or how overall well-being is affected over time by disease, disability or other health issues - in children with epilepsy.

The study found that verbal, emotional difficulty and behavioral problems were associated with a lower health-related quality of life more than other factors, including frequent and intense seizures.

Marianne Hrabok, PhD, of the Alberta Children’s Hospital Research Insititute in Calgary, Alberta, Canada, and colleagues studied 90 children with epilepsy at a children’s hospital.

The number and frequency of seizures in the children varied. Thirty-seven percent of children had fewer than one seizure a month while 15 percent had more than one seizure a day.

Verbal skills and health-related quality of life assessments were examined. The researchers also looked at intellectual function, executive function, behavior and ability to adapt.

Details on socio-demographic factors and neurological status were included in the study.

Gender, age and socioeconomic status are examples of socio-demographic factors. Number of antiepileptic drugs and seizure severity are examples of neurological status.

The researchers found that health-related quality of life was not associated with socio-demographic and neurologic factors.

However, neuropsychological factors - including verbal memory, IQ, executive function, emotional and behavioral function and adaptability - were associated with health-related quality of life. Memory, emotional function and behavioral function had a particular relationship to health-related quality of life.

Those with low verbal memory had a two times greater risk of low health-related quality of life than those who did not have low verbal memory. Those with emotional and behavioral difficulty had a 10 times greater risk of low health-related quality life than those without the difficulty.

Having both low verbal memory and emotional and behavioral difficulty resulted in a risk 17 times greater than not having those difficulties.

The study authors believe these results showed the importance in neuropsychological assessment. Identifying those with poor memory and emotional function could help doctors identify those more likely to have a low health-related quality of life.

The authors suggested that psychosocial interventions for children with epilepsy include a team of health professionals with varying disciplines, an emphasis on involvement of the parents, psychological education, cognitive and behavioral strategies and the development of coping skills. Past studies have shown that a six-week program that includes these factors can improve health-related quality of life.

The study was published in Pediatrics. The research received no external funding. The authors did not report any conflicts of interest.

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Ten Things I Wish Someone Told Me About Parenting a Child with Special Needs

My thanks to Liane Kupferberg for an excellent article with really good advice. - JR

Ten Things I Wish Someone Told Me About Parenting a Child with Special Needs

By Liane Kupferberg Carter at 9:47 am

Liane and her son.

As part of our month-long series dedicated to Jewish Disability Awareness Month, Liane shares advice for those just starting out on the special needs journey.

I’m a proud member of a tribe. No, not just that tribe. I mean the tribe of special needs parents. There’s no way you’d spot us in a crowd. But even without a secret handshake, special needs parents manage to find each other. Maybe it’s that unmistakable look of exhaustion and resolve many of us wear. Whatever it is, I’ve been part of this particular tribe for 20 years.

Even after all this time, I still sometimes stop myself and ask, “How in the world did I get here?” When my son was initially diagnosed with autism and epilepsy years ago, I didn’t know anyone else with a child like him. That was back in the dark ages, before the internet. There were no websites or blogs to turn to for information and support. There was so much I didn’t know, and so much I was desperate to learn; I could have used advice from a seasoned tribal elder.

Now I’m that mom. The one with some mileage on her. There’s no road map to navigate raising a child with special needs, but here are some pointers I wish I’d had when I first set out on this journey.

1. You are the expert on your child. No one else. Not your child’s doctor, his teacher, his neurologist, and certainly not your Great Aunt Gussie who raised 10 kids of her own. Listen respectfully to them, but remember they are experts in their own spheres, not yours. All of them–therapists, family, friends–go home at the end of the day. You are in it for the long haul, and you know your child better than anyone.

2. You are parenting a person, not “treating” a cluster of “symptoms.” When your child is first diagnosed, you’re going to hear a lot about the deficits–all the things your child isn’t doing. Don’t lose sight of the fact that behind the “special needs” label there is the same wonderful child you had before the diagnosis, who needs your guidance and love. There’s a saying so popular in the autism community that it is practically a cliché: “Once you’ve met one person with autism, you’ve met one person with autism.” Your child is unique. Yes, you will get all caught up in searching out treatments and therapies, but please take the time to enjoy him right now, because he won’t be a child forever. Don’t let your fears of the future rob you of the pleasures of the present.

3. People will stare. This will eat at you in the beginning. It’s natural to feel uncomfortable, resentful, even mortified. It is also a natural instinct for people to look at anything that’s a little out of the ordinary. Your child’s quirky behaviors in public may draw attention, and what if they do? Stop worrying about it so much. Who cares what strangers think? And I can promise you this: you will learn to never, ever judge any other parent whose kid acts up in public. Eventually you will figure out how to handle people’s inappropriate questions. I’ll never forget how taken aback I was at a wedding 15 years ago when my husband’s uncle abruptly asked, “Is there any hope for your son?” Sometimes people may imply that you just aren’t trying hard enough. Or they will offer unsolicited advice, or press the latest miracle cure on you. Worst of all, they will talk about your child right in front of him. Don’t let them. And don’t you do it either. Your child may not be verbal (yet), but his ears are working just fine.

4. Take care of yourself. Really. I’m not talking about a trip to Canyon Ranch. A study released a couple of years ago found that autism moms have stress levels similar to combat soldiers. I know there’s nothing you wouldn’t do for your child, but you count too and you’re no good to anyone if you don’t stay healthy and strong. Physically and mentally. Medication is there for a reason. No, not for your child. For you. Don’t be afraid to ask for help if you need it. Because as all special needs parents know, we need to live forever.

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Texas bill will limit full-contact football practices

A new bill in Texas would reduce the amount of full-contact football practices making football practices safer for the players and less likely to have a concussion.

Even on the football field, lessons in physics are inescapable. When two football players collide, the force can equal that of a head smashing against a wall at 20 mph. Hits that serious can cause concussions or more serious brain injuries.

If national averages hold true, about 8,000 of the 168,000 high school football players in Texas will be diagnosed with concussions each year, and untold numbers more will suffer head injuries that aren’t discovered.

“There are a number of horror stories out there about concussions,” said state Rep. Eddie Lucio III, D-Brownsville. “There’s got to be a balance of continuing to play the game at an optimal level and providing safety for the kids.”

Having already successfully pushed laws to make helmets safer and compel schools to safely treat concussions, Lucio has now filed legislation to reduce violent collisions in high school and middle school football by restricting full-contact practices to just one per week.

Right now, the University Interscholastic League — which oversees extracurricular activities for Texas’ public schools — has rules limiting full-contact practices during the off-season. Once the season begins, however, full-contact practices are allowed at all times during the 8 hours a week teams may practice. The UIL set up a program to address concussions in 2005 and has been actively updating it to fit recommendations from its medical board, which receives injury information from selected schools but doesn’t keep statewide concussion statistics.

Lucio cites a Purdue University study finding that repeated blows to the head still change brain activity, even if the individual hits aren’t that serious. Researchers assert that repetitive hits, not just one strong blow, can lead to concussions. By decreasing full-contact practices, Lucio said he hopes to limit those blows and give the brain the proper time to heal.

“If you don’t allow (a) muscle or bone to heal, it’s going to break,” he said. “The same thing is relative to the brain. It can only heal itself at a certain rate, and any additional hits could cause more damage.”

Lucio is still refining his definition of “full-contact” and plans to meet with football coaches this weekend to hash out details of the bill.

Some coaches, however, are concerned that fewer full-contact practices could actually increase concussion risks.

Practicing the fundamentals of safe tackling helps build muscle memory, and athletes can benefit from repetition, said Joe Willis, head football coach and athletic coordinator at Cedar Park High School.

“If you only practice those (fundamentals) once a week, you are moving in the opposite direction of what logic would tell you,” he said. “A kid can’t learn without the experimentation phase.”

Coach of last year’s Class 4A Division II state champions, Willis said Lucio’s bill might be a politically smart move from someone who has never played the game, but he fears it would limit the ability of coaches to teach proper fundamentals.

“I’ve always felt like good coaching prevents those things,” Willis said. “…If you have one day (of full-contact practice), and you go out there with bad technique on that one day, you might get a concussion anyway.”

Not all football coaches share Willis’ concerns. Lake Travis High School head coach Hank Carter said that his team already doesn’t tackle players to the ground during regular season practice to limit injuries.

Concussion awareness has taken center stage over the past few years as more stories about brain injuries trickle out from former players. Former Chicago Bears safety Dave Duerson shot himself in the chest in 2011 to preserve his brain for science. Autopsies of Duerson and other former players found evidence of chronic traumatic encephalopathy, or CTE, a degenerative brain disease linked to brain trauma.

Both the NFL and the Ivy League agreed to limit full-contact practices in 2011 in reaction to public outcry over player safety. The NFL allows only 14 for the entire regular season, the Ivy League two per week. Lucio said he believes that stringent protective measures like these should be in place for the youngest athletes who haven’t finished physical development and don’t have the ability to lobby for themselves.

“We can’t sacrifice (students’) physical or mental health long term,” he said. “It’s got to be a healthy marriage between the two, which is a safe environment to play in but to still play the game like it’s meant to be played.”

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What Are Common Sleep Problems in Toddlers?

This article discusses five common sleep issues in toddlers such as breathing pauses, sweating, nightmares, teeth grinding, and twitching, jerking and restlessness. This article also gives solution to the sleep problems.

It’s a lovely idea to think you can put your toddler to bed and night and not worry about them until morning. But as many parents of toddlers already know all too well, that’s not always the case.

Things like teeth grinding, breathing pauses, sweating, twitching and jerking, and nightmares can keep toddlers from getting a restful night’s sleep, and when they don’t sleep well or enough, it can lead to problems during the day.

Here are five common toddler sleep problems, according to BabyCenter.com, as well as potential solutions for all of them:

Breathing Pauses

Some toddlers might experience breathing pauses while they’re asleep. It could be a sign of sleep apnea, which, according to the Mayo Clinic, is a potentially serious sleep disorder.
However, occasional breathing pauses (along with snoring and snorting) aren’t necessarily a cause for concern. Breathing patterns can change during sleep and many toddlers also sigh in their sleep, which might make them appear as if they’ve stopped breathing for a brief time, but it can, in fact, be normal.
If you suspect your toddler might have sleep apnea, a doctor should be consulted so that potential complications such as a heart problem can be diagnosed and treated.

Sweating

Despite the room temperature being perfect comfortable and their bedding and pajamas being seasonally appropriate, some toddlers will still sweat enough at night to wake up soaked through.
Nighttime perspiration is usually nothing to worry about because it’s probably a sign that the body is "restoring itself". For toddlers who sweat a lot a night, light cotton clothes are recommended for sleeping and rooms should be kept on the cool side.
Livestrong.com advises that “if a toddler is sweating excessively and it appears unrelated to body temperature control, speak to your pediatrician to rule out medical conditions like hyperhidrosis.”

Nightmares

Toddlers aren’t too young to have nightmares, which are often caused by stress and anxiety and occasionally by fevers or medication. They tend to happen later at night when they are deeply asleep.
The Cleveland Clinic advises ensuring toddlers who experience nightmares get adequate sleep, have a bedtime routine that is light, happy and fun, discuss the nightmares during the day, and are comforted, coddled and reassured so that they can sleep more peacefully.

Twitching, Jerking and Restlessness

It’s not uncommon for some toddlers to twitch or jerk or flex their ankles for a few seconds a couple of times a minute for as long as a few hours while falling asleep or while they’re already sleeping. It won’t hurt them, but it might prevent them from getting a peaceful night’s sleep.
The twitches and jerks could be a sign that their levels of iron or folic acid are insufficient, which can be discussed with their pediatrician.
It can also be a sign of restless legs syndrome, which, according to the U.S. National Library of Medicine, is a disorder in which there is an urge or need to move the legs to stop unpleasant sensations.
Techniques such as gentle stretching exercises, massage and warm baths can help muscles relax and lead to a more relaxed night’s sleep.

Teeth Grinding

Bruxism is the medical term for teeth grinding or the clenching of jaws, and according to KidsHealth.org, two to three out of every 10 kids will do it, although most outgrow it.
Kids grind their teeth as a result of tension, anxiety, pain from an earache or teething, allergies, or their teeth not being properly aligned.
Teeth grinding isn’t harmful, but it’s worth mentioning to the dentist to double check there are no problems.
Soothing a toddler who grinds their teeth at bedtime with a bath, backrub or extra cuddling might help alleviate the problem.

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Infant brain's blood flow is regulated differently than an adult brain

Researchers found the blood flow in a developing infant's brain is not the same as an adult's brain. This has many implications for treating developmental disorders.

A new study by Columbia Engineering researchers finds that the infant brain does not control its blood flow in the same way as the adult brain. The paper, which the scientists say could change the way researchers study brain development in infants and children, is published in the February 18 Early Online edition ofProceedings of the National Academy of Sciences (PNAS).

"The control of blood flow in the brain is very important" says Elizabeth Hillman, associate professor of Biomedical Engineering and of Radiology, who led the research study in her Laboratory for Functional Optical Imaging at Columbia. "Not only are regionally specific increases in blood flow necessary for normal brain function, but these blood-flow increases form the basis of signals measured in fMRI, a critical imaging tool used widely in adults and children to assess brain function. Many prior fMRI studies have overlooked the possibility that the infant brain controls blood flow differently."

"Our results are fascinating" says Mariel Kozberg, a neurobiology MD-PhD candidate who works under Hillman and is the lead author of the PNAS paper. "We found that the immature brain does not generate localized blood-flow increases in response to stimuli. By tracking changes in blood-flow control with increasing age, we observed the brain gradually developing its ability to increase local blood flow and, by adulthood, generate a large blood-flow response."

The study results suggest that fMRI experiments in infants and children should be carefully designed to ensure that maturation of blood-flow control can be delineated from changes in neuronal development. "On the other hand," says Hillman, "our findings also suggest that vascular development may be an important new factor to consider in normal and abnormal brain development, so our findings could represent new markers of normal and abnormal brain development that could potentially be related to a range of neurological or even psychological conditions."

Functional magnetic resonance imaging, or fMRI, is one of several brain-imaging methods that measure changes in blood flow to detect the presence and location of neuronal activity. In adults, blood-flow increases occur in specific regions of the brain during a particular task like moving your hand or reacting to a stimulus. FMRI relies upon measuring decreases in deoxygenated hemoglobin resulting from this blood-flow increase to understand which parts of the brain are responsible for different actions and emotions. FMRI and other brain-imaging methods are currently being widely used to explore brain development, and to understand disorders in infants and children including autism and ADHD.

"Until now, we had been studying blood flow in the adult brain," Hillman notes, "but we became interested in several studies that reported odd, sometimes negative, blood-flow responses in newborn and premature infants and decided to carefully explore what was different about the immature brain compared to the adult. Initially, I saw these studies as a way to watch how the adult system assembled itself during development. Then we realized how important our findings were to those using brain imaging to study child development and developmental disorders."

The team used a unique multispectral optical intrinsic signal imaging system (MS-OISI) built in Hillman's lab to perform the research. MS-OISI is a high-speed, high-resolution imaging approach that takes advantage of the different absorption spectra of deoxygenated and oxygenated hemoglobin in order to determine changes in the concentrations of each. The researchers found that, with increasing age, there was a gradual development of a localized increase in blood flow, while a strong, delayed decrease in flow was consistently present. Only by adulthood was the positive increase able to balance the decrease in flow.

"Our results suggest that the infant brain might not be able to generate localized blood- flow increases, even if there is neuronal activity occurring, and that the development of blood- flow control occurs in parallel with early neuronal development," says Kozberg. "This could suggest that fMRI studies of infants and children may be detecting changes in both vascular and neuronal development -- in fact, vascular development may be an important new factor to consider in normal and abnormal brain development."

The team also found that the younger age groups were highly sensitive to blood pressure increases in response to stimulation and that these increases can cause large increases in blood flow across the brain. "This finding indicates that the newborn brain is also unable to regulate its overall blood-flow levels," Kozberg explains. "This could explain earlier fMRI results in infants and children that were sometimes positive and sometimes negative, because it is difficult to tell whether blood pressure increases are occurring in infants and children. This result suggests that great care should be taken in setting stimulus thresholds in young subjects."

The researchers add that, since the newborn brain appears to be able to sustain itself without tightly controlled blood flow, their findings suggest that the infant brain may be intrinsically more resistant to damage due to a lack of oxygen than the adult brain. "This could be an important property to understand, both in terms of understanding how best to treat blood-flow problems in the newborn infant brain, which can cause lifelong problems such as cerebral palsy, and to potentially better understand how to treat the adult brain in conditions such as stroke," Hillman observes.

"Our lab operates at the intersection of neuroscience and engineering," continues Hillman." Not only do we develop the imaging systems that let us investigate the living brain in new ways, but like all engineers, we're fascinated with figuring out 'how things work,' and the brain is no exception."

Next steps for Hillman and her team include further defining the cellular mechanisms underlying the developing hemodynamic response at a cellular and microvascular level, using methods such as high-speed and multi-plane in-vivo two-photon microscopy, another technique developed in the lab. They're particularly interested in tracking changes in neuronal activity, microvascular architecture and connectivity, and the distribution and activity of other cellular populations thought to be associated with neurovascular coupling as a function of development.

"This will help us understand how the neonatal brain is different, and better understand how mature blood-flow control mechanisms in the adult brain work," says Kozberg. Adds Hillman, "We are also keen to take this research into the clinic and explore whether our findings could improve diagnosis and monitoring of newborn infants. Our findings so far feel like just the tip of the iceberg. There is so much more for us to do now to understand why the infant brain is so different, and how we can use our findings to improve understanding of a wealth of devastating childhood and developmental conditions."

This research was supported by grants and student fellowships from the National Institute of Neurological Disorders and Stroke, the National Eye Institute, the National Science Foundation, the National Defense Science and Engineering Graduate Fellowship, the Medical Scientist Training Program, and the Human Frontier Science Program. Hillman is also a member of the Columbia University graduate program in Neurobiology and Behavior and the Kavli Institute for Brain Sciences.

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News about use of codeine after adenotonsillectomy. JR

Post-Surgery Codeine Puts Kids at Risk

Children are often prescribed codeine for pain relief after surgery to remove their tonsils or adenoids to treat chronic tonsillitis or sleep apnea, a condition in which breathing problems make it hard for them to sleep soundly.

However, some children have died after being given codeine in amounts that are within the recommended dose range.

The Food and Drug Administration (FDA) is taking steps to warn about the use of codeine to relieve children's pain after surgery to remove their tonsils or adenoids.

In August 2012, FDA warned the public that this danger exists for children who are "ultra-rapid metabolizers" of codeine, meaning that their liver converts codeine to morphine in higher than normal amounts.

Since then, FDA has conducted a comprehensive safety review of codeine use in children. A search of FDA's Adverse Event Reporting System (AERS) database from 1969 to May 1, 2012 identified 10 deaths and three overdoses associated with codeine. Many of these children were recovering from a surgery to remove their tonsils or adenoids.

A new boxed warning—FDA's strongest warning—will be added to the drug label of codeine-containing products about the risk of codeine to manage pain in children after a tonsillectomy and/or adenoidectomy. (The drug label is the written material that accompanies a prescription medication.)

FDA strongly recommends against the use of codeine to manage pain in children after a tonsillectomy and/or adenoidectomy. The agency asks health care professionals to use an alternate pain reliever.

In addition, parents and caregivers need to be aware of the risks of codeine treatment after tonsillectomy or adenoidectomy and should ask for a different pain medicine if their child is prescribed codeine in that setting

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The Problem 

Codeine is an opioid pain reliever—a narcotic medication—used to treat mild to moderate pain. It is also used to reduce coughing, usually in combination with other medications. Codeine is available by prescription either alone or in combination with acetaminophen or aspirin, and in some cough and cold medications.

Codeine is converted to morphine in the liver by an enzyme. Some people have genetic variations that make this enzyme over-active, causing codeine to be converted to morphine faster and more completely than in other people. These ultra-rapid metabolizers are more likely to have higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal.

From one to seven in every 100 people are ultra-rapid metabolizers, but they are more common among some ethnic groups. Twenty-nine percent of North African and Ethiopian populations are ultra-rapid metabolizers, and about 6 percent of African American, Caucasian and Greek populations are also affected.

The only way to know if someone is an ultra-rapid metabolizer is to do a genetic test. There are FDA-cleared tests to check for ultra-rapid metabolism.

The cases occurred in children who showed evidence of being ultra-rapid metabolizers. The children ranged in age from 21 months to 9 years old. All of the children received doses of codeine that were within the typical dose range, meaning that they were not given extra amounts of the medication.

In these cases, the signs of morphine overdose developed within one to two days after the children started taking codeine.

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Signs of Trouble 

The new changes to the codeine label warn health professionals about the use of codeine after tonsillectomy and/or adenoidectormy. FDA says that codeine should only be prescribed to children with other types of pain if the benefits are expected to outweigh the risks.

The agency warns that when prescribed to treat pain, codeine should not be given on a schedule, but only when the child needs relief from pain. Children should never receive more than six doses in a day.

Parents and caregivers should watch children receiving codeine for pain closely for signs of morphine overdose. There are a number of symptoms to watch for, says Bob Rappaport, M.D., director of the Division of Anesthesia, Analgesia and Addiction Products (DAAAP) in FDA's Center for Drug Evaluation and Research. If your child shows these signs, stop giving the codeine and seek medical attention immediately by taking your child to the emergency room or calling 911:

• Unusual sleepiness, such as being difficult to wake up
• Disorientation or confusion
• Labored or noisy breathing, such as breathing shallowly with a "sighing" pattern of breathing or deep breaths separated by abnormally long pauses
• Blueness on the lips or around the mouth

FDA Drug Safety Communication: Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy

This update is in follow-up to the FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death issued on 8/15/2012.

 View and print full DSC - DSC Update on Codeine 02-2013 [PDF -116KB] 

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• Additional Info
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• Additional Info
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• Data
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Safety Announcement

[2-20-2013] The U.S. Food and Drug Administration (FDA) is updating the public about new actions being taken to address a known safety concern with codeine use in certain children after tonsillectomy and/or adenoidectomy (surgery to remove the tonsils and/or adenoids). Deaths have occurred post-operatively in children with obstructive sleep apnea who received codeine for pain relief following a tonsillectomy and/or adenoidectomy. Codeine is converted to morphine by the liver.  These children had evidence of being ultra-rapid metabolizers of codeine, which is an inherited (genetic) ability that causes the liver to convert codeine into life-threatening or fatal amounts of morphine in the body.

A new Boxed Warning, FDA’s strongest warning, will be added to the drug label  of codeine-containing products about the risk of codeine in post-operative pain management in children following tonsillectomy and/or adenoidectomy. A Contraindication, which is a formal means for FDA to make a strong recommendation against use of a drug in certain patients, will be added to restrict codeine from being used in this setting. The Warnings/Precautions, Pediatric Use, and Patient CounselingInformation sections of the drug label will also be updated.

In August 2012, FDA announced it was reviewing the safety of codeine due to cases of deaths and serious adverse events in children who took the drug after a tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine. FDA conducted a comprehensive safety review to identify additional cases of overdose or death in children taking codeine and to determine if these adverse events occurred in any other treatment settings. Many of the cases of serious adverse events or death occurred in children with obstructive sleep apnea who received codeine after a tonsillectomy and/or adenoidectomy (see Data Summary). Since these children already had underlying breathing problems, they may have been particularly sensitive to the breathing difficulties that can result when codeine is converted in the body to high levels of morphine. However, this contraindication applies to all children undergoing tonsillectomy and/or adenoidectomy because it is not easy to determine which children might be ultra-rapid metabolizers of codeine.

Health care professionals should prescribe an alternate analgesic for post-operative pain control in children who are undergoing tonsillectomy and/or adenoidectomy. Codeine should not be used for pain in children following these procedures.

For management of other types of pain in children, codeine should only be used if the benefits are anticipated to outweigh the risks.

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