Monday, November 30, 2015

Dummheit 3

Stephanie Messenger is an Australian author of self-published educational books for children, such as Don’t Bully Billy and Sarah Visits a Naturopath. In 2012, she published a book that, according to promotional materials, “takes children on a journey to learn about the ineffectiveness of vaccinations and to know they don’t have to be scared of childhood illnesses, like measles and chicken pox.” The blurb on the back of the book talks about how nowadays we’re bombarded with messages urging us to fear diseases, from people who have “vested interests” in selling “some potion or vaccine.”
 
Messenger called the book Melanie’s Marvelous Measles. Perhaps she drew inspiration from the beloved British children’s author Roald Dahl’s George’s Marvellous Medicine. Which would be ironic, given Dahl’s own feelings about measles, which he wrote about in 1986.
Olivia, my eldest daughter, caught measles when she was seven years old. As the illness took its usual course I can remember reading to her often in bed and not feeling particularly alarmed about it. Then one morning, when she was well on the road to recovery, I was sitting on her bed showing her how to fashion little animals out of coloured pipe-cleaners, and when it came to her turn to make one herself, I noticed that her fingers and her mind were not working together and she couldn’t do anything.
“Are you feeling alright?” I asked her. “I feel all sleepy,” she said.
In an hour she was unconscious. In twelve hours she was dead. The measles had turned into a terrible thing called measles encephalitis and there was nothing the doctors could do to save her.
In 1962, when the measles took Olivia’s life, there was no vaccine. Practically everyone caught the measles at some point in childhood. Most recovered without any lasting damage, but it killed around a hundred children in the United Kingdom and more than four hundred in America every year, and put tens of thousands more in the hospital, leaving some blind or brain-damaged. When a vaccine was licensed in the United States a year later, in 1963, the number of people who caught measles plummeted by 98 percent. “In my opinion,” Dahl concluded, “parents who now refuse to have their children immunized are putting the lives of those children at risk.”...

The falling vaccination rates prompted outbreaks of the diseases that the vaccine prevents—particularly, since it’s so highly contagious, measles. The first outbreak was in Dublin in 2000, where vaccination rates were already lower than in the United Kingdom. Almost sixteen hundred cases of measles were reported. More than a hundred children were admitted to hospital with serious complications, and three died. A thirteen-year-old boy died in England in 2006, becoming the first person to die of measles in England since 1994. In 2008, measles was declared endemic in the United Kingdom for the first time in fourteen years. In 2012 there were more than two thousand cases of measles in England and Wales—mostly affecting children and teenagers whose parents had declined the MMR vaccine years earlier. In 2013, another outbreak in Wales infected more than a thousand people, hospitalizing eighty-eight, and killing a twenty-five-year-old man...

That all looks pretty bad, I think it’s fair to say, but we shouldn’t necessarily dismiss the hypothesis that MMR somehow causes autism on the basis of Wakefield’s behavior alone. Since his paper was published, dozens of independent, large, well-conducted studies, involving hundreds of thousands of children across several continents, have found no association whatsoever between the MMR vaccine and autism. As Paul Offit, a pediatrician and immunologist, has pointed out, we still don’t know for sure exactly what causes autism, but by now we can say with considerable certainty that vaccines can be crossed off the list of suspects...

In 1973, a British doctor called John Wilson gave a presentation at an academic conference in which he claimed that the pertussis component of DPT was causing seizures and brain damage in infants. The research was based on a small number of children, and it has since emerged that many of the children were misdiagnosed, and some hadn’t even received the DPT vaccine. Regardless, Wilson took his findings to the media, appearing on prime-time television in a program that contained harrowing images of sick children and claimed that a hundred British children suffered brain damage every year as a result of the DPT vaccine. Uptake of the DPT vaccine fell from around 80 percent at the beginning of the decade to just 31 percent by 1978. This was followed by a pertussis epidemic during 1978 and ’79, in which a hundred thousand cases of whooping cough were reported in England and Wales. It’s estimated that around six hundred children died in the outbreak.

Despite flaws in Wilson’s study, as well as a growing number of studies that found no evidence of the alleged link between DPT and brain damage, by the early eighties the fear had spread to America...

So the current epidemic of fear over the MMR vaccine is in many ways simply an extension of the vaccine anxiety that blossomed in the 1970s. But it didn’t start there. In fact, people have been worried about the safety of vaccines—and the motives of the people who make and sell them—since the discovery of the very first vaccine...

By 1820, millions of people had been vaccinated in Britain, Europe, and the United States, and the number of people dying from smallpox was cut in half.

Not everyone was impressed. There immediately arose some sporadic opposition to the vaccine. Objections were occasionally raised on religious grounds—to vaccinate oneself, some argued, was to question God’s divine plan. Others objected for economic reasons, or simply out of disgust at a vaccine derived from sick cows, coupled with distrust of the doctors who administered them. By 1800, Jenner was moved to defend his vaccine from detractors, writing “the feeble efforts of a few individuals to depreciate the new practice are sinking fast into contempt.” His optimism was misplaced...

So vaccine anxiety was a side effect of the very first vaccine, and the symptoms have never quite cleared up. Perhaps the most remarkable thing about the long-standing unease about vaccines is how little the arguments have changed over the centuries. Jenner’s critics created elaborate cartoons depicting doctors as unfeeling monsters, intent on sacrificing innocent, helpless children. Twenty-first-century anti-vaccinationists write blog posts with titles like “Doctors want power to kill disabled babies.” Nineteenth-century activists claimed that the smallpox vaccine contained “poison of adders, the blood, entrails, and excretion of bats, toads and suckling whelps” and fought for their right to remain “pure and unpolluted.” The modern-day “green our vaccines” movement doesn’t go so far as to say vaccines contain entrails, but they still misconstrue vaccines as containing “toxins” including antifreeze, insect repellent, and spermicide. And, as Paul Offit has pointed out, the current concerns about MMR somehow causing autism are about as plausible, biologically speaking, as the claim, widely reported in the early 1800s, that the smallpox vaccine caused recipients to sprout horns, run about on all fours, and low and squint like cows.

And throughout it all, there have been theories alleging a vast international conspiracy to trump up the dangers of the diseases that vaccines, to hide the truth about vaccine side effects, and to ensure profits for Big Pharma and the government...

Thanks to a small but vocal minority of dedicated anti-vaccinists, the Internet is rife with conspiracy-laced misinformation urging us not to trust vaccines. Making matters worse, the media often portrays the controversy with a false sense of balance. Most parents have heard the claims about autism and vaccines, and, according to a recent study, merely reading anti-vaccine conspiracy theories can reduce parents’ willingness to have their children vaccinated.

The science is clear: Vaccines do not cause autism. But conspiracy theories erode our trust in science, allowing controversy to linger long after the questions have been settled.

http://www.salon.com/2015/11/29/what_the_hells_wrong_with_us_autism_vaccines_and_why_some_people_believe_jenny_mccarthy_over_every_doctor/

Saturday, November 28, 2015

Snake oil

The government finally is cracking down on the unregulated dietary supplement industry.
Principal Deputy Assistant Attorney General Ben Mizer took the podium Tuesday to announce a multi-faceted approach to “stem the tide of unlawful dietary supplements” in the U.S.—one that’s motivated by a spate of lawsuits and severe illness resulting from the substances.

According to the National Institutes of Health the “majority of adults” take a dietary supplement either every day or occasionally. Since the Federal Drug Administration does not approve the substances, the $40 billion industry remains unregulated, which leaves room for companies to hide a cocktail of ingredients within their product.

A study from April of this year published in the Drug Testing and Analysis journal found the presence of synthetic speed that’s never been tested in humans in 11 different supplements. A 2014 study published in the Journal of the American Medical Association found “two thirds of supplements previously recalled by the FDA were still tainted with prescription drugs.”
 
Beyond unethical, the hidden ingredients can prove widely dangerous.

A paper published this October in The New England Journal of Medicine found an estimated 23,000 emergency room visits each year to be related to dietary supplements. Twenty-eight percent involved young adults between the ages of 20-34, must of whom suffered cardiovascular problems.

Tuesday’s announcement marks the biggest effort to clean up the supplement industry thus far.
The “sweep of actions” to be taken in the following months includes plans from the Federal Trade Commission, the FDA, the U.S. Postal Services, the Department of Defense, and the Anti-Doping Agency.

On the legal front, Mizer said the attorney general’s office intends to pursue civil and criminal cases against the makers of these products for knowingly selling dangerous drugs. He announced a new case against the maker of a workout/weight loss supplement, USP Labs. Sold under names like Jack3d and OxyElitePro, the best-selling supplement is made with chemicals from China that Mizer said the company knew were dangerous and used anyway.

After falsifying documents and doctoring the packaging, USP Labs began selling the supplements to the American public, some of whom ended up needing liver transplants to survive. When the FDA instructed the company to discontinue sales, it refused. “The allegations against USP Labs at should serve as a wake-up call to the supplement industry,” said Mizer.

Last month, Oregon’s Attorney General Ellen Rosenblum filed a lawsuit against GNC, one of the largest supplement-makers in the nation, claiming that it “knowingly sold products spiked with two synthetic drugs.” One of the two ingredients, picamilon, is a Russian drug used to treat migraines and brain damage. GNC responded to say that it was committed to providing customers with the “highest quality supplements” using the “purest ingredients.”

Howard Sklamberg, the FDA’s Deputy Commissioner for Global Regulatory Operations and Policy, spoke next, calling dietary supplements one of the “most challenging” areas for his organization to regulate. He said the FDA plans to take “vigorous action” against false claims and to crack down on false labeling that hides pharmaceutical ingredients.

Next up was Gary R. Barksdale, Acting Deputy Chief Inspector of the U.S. Postal Service, who said his team began issuing search warrants nationwide on Friday. Reilly Dolan, Acting Deputy Director for the FTC’s Bureau of Consumer Protection, said his organization plans to attack “deceptive and unfair” marketing practices in the industry.

Dolan said that while some supplements that make up the $40 billion industry do work, others are “nothing more than 21st century snake oil.” To combat the marketing tactics, his team is announcing two settlements, twenty warning letters, and 11 other cases. He condemned “disreputable companies” for preying on health issues of average Americans, from obesity to drug addiction, and convincing them that their supplements could fix their problems.

Dr. David J. Smith, Deputy Assistant Secretary of Defense for Health Readiness Policy and Oversight, said the DOD and the Military Health System are in “full compliance” with the DOJ. He called the issue of supplements a “top threat” in the U.S. Military, noting that 70 percent of active duty service members take some form of supplement. Smith commended the group for taking on the issue, and said his goal was to “keep our service men fit to serve.”

The last to speak was Amy Eichner, The U.S. Anti-Doping Agency’s Special Advisor on Drugs and Supplements—who said that her demographic is one of the supplement industry’s key markets. “Elite athletes, all athletes, including recreational level, youth athletes, masters athletes, even the kids on playing fields in your neighborhoods are very heavily targeted by dietary supplement companies…” said Eichner. “The actions announced today are a real win for clean athletes.”

http://www.thedailybeast.com/articles/2015/11/17/the-40-billion-snake-oil-industry.html#
 

Raisin test

A simple test using a raisin can predict how well a toddler will perform academically at age eight, according to research conducted at the University of Warwick.

Using just the piece of dried fruit and a plastic cup they have devised a test based on how long a 20-month old child can wait to pick up a raisin in front of them.

The toddlers were given a raisin that was placed under an opaque cup within easy reach. After three training runs toddlers were asked to wait until they were told (60 seconds) they could touch and eat the raisin. During the study it was found that those who were born very prematurely were more likely to take the raisin before the allotted time. In a follow on study the academics found that those who couldn't inhibit their behavior as toddlers weren't performing as well in school as their full-term peers seven years later.

Senior author, Professor Dieter Wolke, who is based at the University of Warwick's Department of Psychology and at Warwick Medical School, said: "An easy, five-minute raisin game task represents a promising new tool for follow-up assessments to predict attention regulation and learning in preterm and term born children. The results also point to potential innovative avenues to early intervention after preterm birth."

The study Preterm Toddlers' Inhibitory Control Abilities Predict Attention Regulation and Academic Achievement at Age 8 Years will be published in the Nov. issue of The Journal of Pediatrics. To view the online version of the study visit http://www.jpeds.com

Data were collected as part of the prospective Bavarian Longitudinal Study which began in Germany in 1985 and is still underway. During the study, 558 children born at 25 to 41 weeks gestation were assessed for self-control once they were 20 months old. The results of those born preterm 25-38 weeks were compared to those born a healthy full term between 39-41weeks.

Around age eight, the same children were evaluated by a team of psychologists and pediatricians using three different behavior ratings of attention from mothers, psychologists and the whole research team. Academic achievement -- including mathematics, reading and spelling/writing -- was assessed utilizing standardized tests.

The findings concluded that the lower the gestational age, the lower a toddler's inhibitory control-- and the more likely those children would have poor attention skills and low academic achievement at eight years old.

Julia Jaekel, lead author of the study and honorary research fellow at the University of Warwick and assistant professor of child and family studies at University of Tennessee, Knoxville, said: "This new finding is a key piece in the puzzle of long-term underachievement after preterm birth"
.
The academics believe that being able to identify cognitive problems early on could result in the development of specialist, tailored education to help prevent these children underachieving at school and later on as adults.

Thursday, November 26, 2015

Congenital insensitivity to pain

The girl who feels no pain was in the kitchen, stirring ramen noodles, when the spoon slipped from her hand and dropped into the pot of boiling water. It was a school night; the TV was on in the living room, and her mother was folding clothes on the couch. Without thinking, Ashlyn Blocker reached her right hand in to retrieve the spoon, then took her hand out of the water and stood looking at it under the oven light. She walked a few steps to the sink and ran cold water over all her faded white scars, then called to her mother, “I just put my fingers in!” Her mother, Tara Blocker, dropped the clothes and rushed to her daughter’s side. “Oh, my lord!” she said — after 13 years, that same old fear — and then she got some ice and gently pressed it against her daughter’s hand, relieved that the burn wasn’t worse.
 
“I showed her how to get another utensil and fish the spoon out,” Tara said with a weary laugh when she recounted the story to me two months later. “Another thing,” she said, “she’s starting to use flat irons for her hair, and those things get superhot.”...
 
When Ashlyn was 2, her mother had to wrap her hands to keep her from biting them.Credit Tara Blocker 

Without lifting her eyes from the crochet hooks in her hands, Ashlyn spoke up to add one detail to her mother’s story. “I was just thinking, What did I just do?” she said...

When she made an egg sandwich on the skillet, she pressed her hands onto the bread as Tara had taught her, to make sure it was cool before she put it into her mouth. She can feel warmth and coolness, but not the more extreme temperatures that would cause anyone else to recoil in pain.

There was the time she burned the flesh off the palms of her hands when she was 2. John was using a pressure-washer in the driveway and left its motor running; in the moments that they took their eyes off her, Ashlyn walked over and put her hands on the muffler. When she lifted them up the skin was seared away. There was the one about the fire ants that swarmed her in the backyard, biting her over a hundred times while she looked at them and yelled: “Bugs! Bugs!” There was the time she broke her ankle and ran around on it for two days before her parents realized something was wrong...

When she was born, she didn’t cry. She barely made a noise, staring out from her swaddling with a blank red face. When she developed terrible diaper rash, so raw that it made Tara wince to even wash her, the pediatrician gave instructions to change her formula and put cream on the rash and keep it dry. “I kept thinking, But she’s not crying,” Tara said. “The doctors dismissed it, but we’re thinking, What’s going on?”...

 At 6 months, Ashlyn’s left eye was swollen and bloodshot. The doctor suspected pink eye, but Ashlyn didn’t respond to the treatment, so they went to an ophthalmologist, who found a massive corneal abrasion. “And Ashlyn is just sitting there, happy as can be,” Tara recalled. The ophthalmologist assumed she had no corneal sensation in her eyes, and referred them to the Nemours Children’s Clinic in Jacksonville, Fla. It took a while to get an appointment, and before they made it to Jacksonville, Ashlyn rubbed big red splotches on her nose and almost chewed off part of her tongue with her emerging teeth...

“The doctor told us we were the only ones out there,” Tara said. “That it was so rare. He said to keep an eye on her and that they didn’t know much about it and couldn’t really be of any help. It was kinda like, ‘Good luck!’ ” ...

Over the next few years, Staud tested Ashlyn’s genetic material and eventually found two mutations in her SCN9A gene. That same gene, mutated in a different way, led to severe pain and chronic pain syndromes...

John and Tara had seen her say, “Ow!” when someone else was hurt. And Ashlyn yelped when her father described the time he put a nail straight through his thumb while he was building a chicken coop, but she had no idea why his face got red and his voice got loud and he held his thumb in the air. She said that over the years she studied the expressions other people made and learned to cringe when someone described something painful.
 
“Girl, what goes through your mind when you see someone hurt?” John asked her.
 
“I feel bad for them,” she said. “Because they go through the pain and I don’t. I would help them.”
 
“Define pain for you,” John said. “What does it mean for you?”
 
“I don’t know.”
“When you see someone else in pain, what do you associate?”
 
“That must really hurt.”
 
“What is hurt?”
 
Ashlyn squinted her eyes, as if in deep thought. She couldn’t answer him.
 
http://www.nytimes.com/2012/11/18/magazine/ashlyn-blocker-feels-no-pain.html?_r=0
  

Shades of Questcor 2

After weeks of criticism from patients, doctors and other drugmakers for hiking a life-saving medicine’s price more than fifty-fold, Turing Pharmaceuticals is reneging on its pledge to cut the $750-per-pill price.

Instead, the small biotech company is reducing what it charges hospitals, by up to 50 per cent, for its parasitic infection treatment, Daraprim. Most patients’ co-payments will be capped at $10 or less a month. But insurers will be stuck with the bulk of the $750 tab. That drives up future treatment and insurance costs.

[Martin Shkreli, chiel executive officer of  Turing Pharmaceuticals and KaloBios Pharmaceuticals, Inc.] The 32-year-old likes sunglasses, golf shirts, the hip-hop artist Eminem, a bottle of 1982 Lafite-Rothschild, and jacking up the price of a pill used by people who suffer from HIV

Daraprim is a 62-year-old pill whose patent expired decades ago. It’s the preferred treatment for a rare parasitic infection, toxoplasmosis, which mainly threatens people with weak immune systems, such as HIV and organ transplant patients, and pregnant women, because it can kill their baby. Dr. Carlos del Rio, chairman of the HIV Medicine Association, called Turing’s changes “just window dressing.”

Turing’s move comes after a pharmacy that compounds prescription drugs for individual patients, Imprimis Pharmaceuticals, started selling a custom-made version for 99 cents per capsule. Those sales weren’t a factor in Turing’s pricing strategy, chief marketing officer Nancy Retzlaff said Wednesday.


Del Rio noted that while hospitals treat many patients initially, most are then treated at home for a couple months, so the lower hospital price doesn’t help.

“This medication can be made for pennies. They need to reduce the price to what it was before,” he said.

http://business.financialpost.com/investing/market-moves/turing-pharmaceuticals-reneges-on-cutting-750-a-pill-drugs-price-but-rivals-new-99-cent-version-is-selling-well

Autism incidence

Is it vaccines? Air pollution? Infections?

Nope. The reason that the latest numbers for autism prevalence among US children have climbed traces largely to a simple change in how interviewers asked a question.

The US Centers for Disease Control and Prevention last conducted the National Health Interview Survey (NHIS) for the years 2011 through 2013. The 2014 survey, though, included a tweak, and that tweak is the reason that autism prevalence climbed from 1.25% to 2.24% in 2014. Not even the most die-hard causation theorist could argue that in a single year or handful of years, something environmental, like vaccines, caused a near-doubling of autism prevalence in children ages 3 to 17 years.

So what underlies the increase?

For the 2011-2013 survey, parents answered a series of three questions. The first asked if their child had intellectual disability. The second asked if their child had any developmental delay. And the third question listed several conditions, from Down syndrome to sickle cell anemia to autism spectrum disorder (ASD), and parents were asked if their child had been diagnosed with any of them. But 2014 brought some tweaks, and those tweaks made a difference. The intellectual disability question came first again. But the second question directly asked parents if their child had an ASD diagnosis. The third question then asked about any other developmental delay. More than 10,000 parents are interviewed in each year of this survey.

The simple change to emphasize the autism question resulted in the near doubling of prevalence from 2011–2013 to 2014. Underscoring that this increase reflects a shift in how parents responded to the questions, the prevalence of ‘other developmental disorders’ dropped in that same time period from 4.84% in 2011-2013 to 3.57% in 2014. Intellectual disability prevalence remained pretty much the same in the two periods, and the collective prevalence for all three conditions (intellectual disability, ASD, and other developmental disorders) also remained stable.

These latest values bring the results of three national surveys of autism prevalence into alignment. In addition to the NHIS, the US also identifies autism prevalence values from the Autism and Developmental Disabilities Monitoring Network (ADDM) and the National Survey of Children’s Health (NSCH). The most recent results from the NSCH put autism prevalence at 1 in 50 children. This latest NHIS prevalence of 1 in 45 converges on that finding, and the agreement among the studies strengthens their conclusions...

Earlier surveys and some research have suggested that autism is four or five times more common in boys than in girls, but the NHIS survey has it as just under 3 times more common in boys (3.29 vs 1.15 in girls)...

One final result to highlight from this survey: The results are similar for age groups, at 2.34 for children ages 3-10 and 2.13 for children ages 11-17. That similarity also suggests some stability across the years in the true prevalence of this condition, whether a child was born in 1998 or in the 21st century.

http://www.forbes.com/sites#/sites/emilywillingham/2015/11/13/you-wont-guess-why-u-s-autism-prevalence-is-now-1-in-45/

Cognitive and behavioral outcomes in NF1

van der Vaart T, Rietman AB, Plasschaert E, Legius E, Elgersma Y, Moll HA;
NF1-SIMCODA Study Group. Behavioral and cognitive outcomes for clinical trials in
children with neurofibromatosis type 1. Neurology. 2015 Oct 30. pii:
10.1212/WNL.0000000000002118. [Epub ahead of print]

Abstract

OBJECTIVE:

To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures.

METHODS:

Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data.

RESULTS:

Strongest mean score deviations from the reference groups were observed for full-scale intelligence (-1.1 SD), Rey Complex Figure Test delayed recall (-2.0 SD), attention problems (-1.2 SD), and social problems (-1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52-0.81) and Child Behavioral Checklist subscales (r range 0.40-0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits.

CONCLUSIONS:

Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1

Courtesy of:  http://www.mdlinx.com/neurology/news.cfm/317

Wednesday, November 25, 2015

Cesarean section and brain development

These immune changes — or perhaps something else about the experience of birth — may affect the brain, too. Castillo-Ruiz and her advisor, neuroscientist Nancy Forger, had noticed a strange spike in cell death right around the time of birth in baby mice. That sounds alarming, but it's not: As the nervous system grows, it overproduces brain cells, only to kill off the ones it doesn't need.
"We were struck by this peak of cell death right at birth," Forger said. It happens across the brain, she said, in the hippocampus, the prefrontal cortex, the hypothalamus and more.

Forger and Castillo-Ruiz wondered if birth itself was kick-starting this process. Some recent work suggests that the immune system plays a role in this cell destruction, and birth is an immunological experience. Not only are babies introduced to mom's microbiome during delivery, but are also exposed to inflammatory signals in the uterus as the process of labor begins.

The researchers bred mice and watched them like hawks 19 days after conception, when delivery was imminent. Forger's team made hourly, round-the-clock checks on the pregnant mothers. When one began to give birth, she selected another mouse at the same point in gestation that wasn't yet in labor. Then she conducted a mouse-y cesarean to deliver that mother's litter. In this way, the researchers could compare the effects of delivery method without any confounding data on gestational length.
The project is still ongoing, but the researchers presented some preliminary results at the annual meeting of the Society for Neuroscience in October. Early analysis of the mice brains suggests that the delivery method mattered. Three hours after birth, baby mice born by C-section show decreased cell death compared with mice born vaginally, she said.

The team has also measured physical development of the offspring. The method of birth didn't seem to affect initial body weight or time of eye-opening in juvenile mice. But later on at weaning age, the researchers observed an increase in body weight in cesarean born mice, which is in line with reports of higher body mass index and risk of adult obesity in humans born by cesarean section, the researchers said.

Looking at the behavior of baby mice, the researchers found that cesarean-born mice made softer cries when separated from their mothers at 9 days old than mice born vaginally. This could be meaningful for a little mouse's life and survival, Forger said, because other research has found that moms pay more attention to the mouse babies when they're louder.

As for the change in the rate of naturally occurring neuronal death, the researchers are planning to get to the bottom of the underlying mechanism. They are now investigating whether the microglia, the immune cells of the brain, have a role in neuronal cell death and whether their function is altered depending on how a baby mouse is born. That focus on a potential mechanism for the changes is a strength of the study, said John Cryan, a neuroscientist at University College Cork who was not involved in the research but who has studied the long-term neurobehavioral effects of cesarean sections and found changes in anxiety and social behavior in mice.

"Early-life manipulations can have long-term effects in sculpting behavior later on, and this is a very important area both in basic science, but also in clinical medicine," Cryan said.
 
The effects of birth aren't all immunological, either — babies about to be born are exposed to a massive flood of hormones during labor. If labor never starts, that hormonal influence never happens. One of these hormones is oxytocin, a poorly understood compound, which nevertheless seems to have a variety of effects in the brain. For example, it has been found to switch the function of the neurotransmitter GABA in mice—In fetal mice brain, GABA has an excitatory influence on neurons. Shortly before delivery, oxytocin triggers a chain of events that causes GABA to have inhibitory actions in the mature brain. This shift doesn't happen in some rodent models of autism, Aix-Marseille University researcher Yehezkel Ben-Ari and colleagues found in a 2014 paper published in the journal Science. Cryan and his colleagues, too, have also looked at the effects of oxytocin exposure on the newborn brain. They found that a post-delivery dose of oxytocin can reverse some of the behavioral effects seen in mice born by C-section, they reported in October at the Society for Neuroscience as well.

In the face all these potential effects just coming to light, other researchers have started to look into ways to make cesareans seem a little bit more like vaginal birth. The World Health Organization estimates that about 10 percent to 15 percent of births need to end in C-section in order to prevent the deaths of both moms and babies. Researcher Maria Dominguez-Bello of the New York University School of Medicine and her colleagues have been conducting an experiment in which a piece of gauze is placed in the vagina of a mother about to undergo a cesarean, and then used to swab the baby's skin after birth. Her research suggests that this strategy can partially restore the baby's skin microbiome to what it would look like after a vaginal delivery.

There are caveats, of course. We still know too little about the long-term, real-world neurological effects of birth in humans, Cryan said. In fact, some mothers may not have a vaginal microbiome you'd want a baby introduced to. In Dominquez-Bello's work, the team tries to control for such unknowns by testing mothers to ensure their vaginal microbiome is Lactobacillus-dominated, strep-B negative and otherwise healthy.

And there are mothers' needs to consider. Choosing the method of giving birth is not just a medical but also a personal decision, which makes it all the more important to continue investigating the true effects of birth methods, so moms can make informed birth choices.

"The last thing we want to do is go blaming moms," Cryan said. But in some places, medical policy has pushed cesarean rates sky-high. In the United States, the C-section rate is about 30 percent. Although this is considered a high rate by medical societies such as The American College of Obstetricians and Gynecologists, rates are even higher elsewhere. In Brazil, for example, 85 percent of private hospital births are done by cesarean, as are 45 percent in public hospitals. Those high numbers make a close look at consequences necessary, Forger said.

https://www.braindecoder.com/vaginal-birth-cesarean-brain-development-1458553654.html#vaginal-birth-cesarean-brain-development-1458553654.html
Courtesy of Doximity

Tuesday, November 24, 2015

One pills makes you larger, and one pill makes you small...

Jürgens TP, Ihle K, Stork JH, May A. "Alice in Wonderland syndrome" associated
with topiramate for migraine prevention. J Neurol Neurosurg Psychiatry. 2011
Feb;82(2):228-9.

Abstract

Various visual and sensory phenomena have been described in migraine with aura. Among those, the 'Alice in Wonderland' syndrome is defined as a distortion of the body image with the patient being aware of its unreal nature. Here, the case of a 17-year-old girl with migraine without aura who developed an 'Alice in Wonderland' syndrome repeatedly on topiramate treatment was presented and potential pathophysiological concepts were discussed.


Evans RW. Reversible palinopsia and the Alice in Wonderland syndrome
associated with topiramate use in migraineurs. Headache. 2006 May;46(5):815-8.

Abstract

Two patients are reported who developed palinopsia while taking topiramate for migraine prevention which resolved or decreased in frequency or duration on lower doses, but recurred or increased in frequency or duration on higher doses. Both patients had complete resolution of palinopsia when topiramate was discontinued. A third patient is described who developed the "Alice in Wonderland" syndrome about 1 week after starting topiramate for migraine prevention with complete resolution of symptoms about 1 month after stopping. Topiramate use may cause palinopsia and may be associated with the Alice in Wonderland syndrome through an unknown mechanism.

Advances in pediatric movement disorders: a field guide

The field of child movement disorders has faced unprecedented development over the last decade. This is largely due to advances in three key areas. The first is neuroimmunology, with the description of new antineuronal surface antibodies associated with specific clinical syndromes, including movement disorders, behavioural abnormalities and epilepsy, in particular anti–N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis. The second is neurogenetics, in which the mounting use of next-generation sequencing enabled prodigious discovery of new genes and an expansion of the phenotypic spectrum for many conditions. The last but equally important comes from advances in nonpharmacological treatment of movement. In this article, we review recent developments putting them into context with the purpose of enabling busy clinicians and researchers to better navigate the swelling literature in this field...

 A UK-wide paediatric surveillance study detected 10 new cases of anti-NMDAR encephalitis over 13 months, giving an incidence of 0.85 per million children per year [95% confidence interval (95% CI) 0.64–1.06]. Previous series of encephalitis of an unknown origin suggest that it may represent up to 4% of these cases....

The presentation is age-dependent. Younger patients have more movement disorders and epilepsy at onset, and less commonly present underlying tumours. In a review of nine cases of infants and toddlers, none had a neoplasm despite investigations. Even adult patients usually present with movement disorders within the first month of presentation. Movement disorders include choreoathetosis, oro-facial dyskinesias and/or limb dyskinesias, varied severity of dystonias and Parkinsonian features. Atypical symptoms such as cerebellar ataxia or hemiparesis are rare but can be present in young children at onset. Most patients present with multiple symptoms....

In addition, herpes simplex virus (HSV) can trigger auto-immunity, which in turn can cause immune-mediated clinical relapses without viral activity on PCR testing or new lesions on MRI, and which often manifest with encephalopathy and treatment-resistant chorea associated with anti-NMDAR antibodies. The clinical implications of these recent findings require careful study. This evidence supports anti-NMDAR autoantibody testing is warranted in HSV relapses, that patients with HSV encephalitis could potentially benefit from concomitant testing and treating for auto-immunity during the early phases of disease to prevent clinical relapses and that prophylactic steroid use in the acute phase of the viral illness might hypothetically protect against future relapses...

Mutations in at least 10 different genes have been associated with neurodegeneration with brain iron accumulation (NBIA)...

AGS, which was described by Jean Aicardi and Françoise Goutières in 1984 as an infantile encephalopathy with basal ganglia calcification and mixed dystonia and spasticity, is now known to be an interferonopathy caused by mutations in at least seven genes associated with nucleic acid metabolism: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and the recently described mutations in IFIH1, a gene that codes for a receptor for viral RNA activating the interferon response...

Genetic heterogeneity, phenotypic pleiotropy and variable expressivity are not mutually exclusive and are in fact becoming the norm in genotype-phenotype correlations. TREX1, for example, which is one of seven genes causing AGS, also causes familial chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leucodystrophy due to its involvement with the immune response...

Many of the genes associated with paediatric movement disorders display significant variability in their expression...In 2012, proline-rich transmembrane protein 2 (PRRT2) was simultaneously described in association with paroxysmal kinesigenic dyskinesia (PKD, OMIM #128200), infantile convulsions and choreoathetosis (ICCA, OMIM #602066) and benign familial infantile seizures (BFIS, OMIM #605751), all dominantly inherited, except for a few autosomal recessive cases...

Genetic heterogeneity, phenotypic pleiotropy and variable expressivity are not mutually exclusive and are in fact becoming the norm in genotype-phenotype correlations. TREX1, for example, which is one of seven genes causing AGS, also causes familial chilblain lupus, systemic lupus erythematosus and retinal vasculopathy with cerebral leucodystrophy due to its involvement with the immune response...

For PRRT2, the most common mutation (a nucleotide insertion leading to a premature stop codon) has been associated with all the phenotypes described, and the only consistent genotype-phenotype correlation described so far is the difference between the milder autosomal dominant cases when compared with the more severe homozygous cases...

In addition to immunological and genetic factors, the role of socio-economic and psychodynamic elements as environmental determinants of paediatric movement disorders has received increased attention. A 13-year longitudinal population study from the UK showed a two-fold risk (odds ratio 2.09, 95% CI 1.38–3.47) of development of chronic tics and Tourette syndrome in children in the lowest tertile of socio-economic status when compared with the highest tertile...Current guidelines for clinical management of Tourette syndrome recommend behavioural therapy and encourage awareness promotion for voluntary management of the abnormal movements and the associated premonitory urges...

Dystonia, of any cause, including cerebral palsy (CP), has a severe impact on childhood; of a sample of 279 out of 294 cases referred for deep brain stimulation (DBS) or intrathecal baclofen (ITB), almost two-thirds referred worsening, one-third remaining as severe and few improving spontaneously...

Use of the Canadian Occupational Performance Measure (COPM) demonstrated meaningful performance and satisfaction in goal-attainment after DBS in all causes of dystonia, including CP and cases of NBIA/PANK2-disease and other disorders, for example glutaric aciduria type 1

  http://journals.lww.com/co-neurology/Fulltext/2015/08000/A_field_guide_to_current_advances_in_paediatric.20.aspx?cid=MR-eJP-AdSales-Lundbeck-Neurology-WCO-NoPromo

Silveira-Moriyama L, Lin JP. A field guide to current advances in paediatric
movement disorders. Curr Opin Neurol. 2015 Aug;28(4):437-46.
 

Lithium therapy in Kleine-Levin syndrome

Leu-Semenescu S, Le Corvec T, Groos E, Lavault S, Golmard JL, Arnulf I.
Lithium therapy in Kleine-Levin syndrome: An open-label, controlled study in 130
patients. Neurology. 2015 Nov 10;85(19):1655-62.

Abstract

OBJECTIVE:

To compare the benefits and risks of lithium therapy vs abstention/other treatments in Kleine-Levin syndrome (KLS).

METHODS:

In a KLS cohort followed in a single center, 130 patients regularly took lithium carbonate (median dose 1,000 mg/day; n = 71; 40 children), valproate (n = 5), contraceptive pill (n = 5), or no treatment (n = 49). The disease characteristics (frequency, mean, and longest durations of episodes, time incapacitated per year) were compared before and after follow-up in the lithium vs abstention groups.

RESULTS:

The time between KLS onset and therapeutic onset was 69 ± 92 months. The patients were then followed up for a mean of 21.5 ± 17.8 months. Before treatment, the 71 patients treated with lithium tended to have a higher frequency of episodes per year (3.8 ± 2.9 vs 2.9 ± 2.6) and had a longer time spent incapacitated (57 ± 51 vs 37 ± 35 days) than the untreated patients. The mean (-8 ± 20 vs 2 ± 13 days) and longest (-18 ± 35 vs -5 ± 13) episode duration, the time spent incapacitated (-37 ± 65 days vs -10 ± 38), as well as the frequency of episodes per year (-2.6 ± 2.9 vs 1.3 ± 2.78) decreased significantly more in the treated than in the untreated patients. Side effects (reported by 50% of the patients) were mild and classical with lithium (tremor, increased drinking, diarrhea, and subclinical hypothyroidism).

CONCLUSIONS:

In this large, prospective, open-label, controlled study, the benefit/risk ratio of lithium therapy is superior to that of abstention, supporting the concept that lithium has anti-inflammatory/neuroprotective effects.

CLASSIFICATION OF EVIDENCE:

This study provides Class IV evidence that for patients with KLS, lithium decreases the frequency and duration of KLS episodes.

Monday, November 23, 2015

PTEN and autism

Frazier TW, Embacher R, Tilot AK, Koenig K, Mester J, Eng C. Molecular and
phenotypic abnormalities in individuals with germline heterozygous PTEN mutations
and autism. Mol Psychiatry. 2015 Sep;20(9):1132-8.

Abstract

PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

Tilot AK, Frazier TW 2nd, Eng C. Balancing Proliferation and Connectivity in
PTEN-associated Autism Spectrum Disorder. Neurotherapeutics. 2015
Jul;12(3):609-19.


Abstract

Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed. Once a germline PTEN mutation is found, and a diagnosis of phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome made, the clinical outlook broadens to include higher lifetime risks for multiple cancers, beginning in childhood with thyroid cancer. First described as a tumor suppressor, PTEN is a major negative regulator of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) signaling pathway-controlling growth, protein synthesis, and proliferation. This canonical function combines with less well-understood mechanisms to influence synaptic plasticity and neuronal cytoarchitecture. Several excellent mouse models of Pten loss or dysfunction link these neural functions to autism-like behavioral abnormalities, such as altered sociability, repetitive behaviors, and phenotypes like anxiety that are often associated with ASD in humans. These models also show the promise of mTOR inhibitors as therapeutic agents capable of reversing phenotypes ranging from overgrowth to low social behavior. Based on these findings, therapeutic options for patients with PTEN hamartoma tumor syndrome and ASD are coming into view, even as new discoveries in PTEN biology add complexity to our understanding of this master regulator.

Courtesy of Cleveland Clinic Children's Pediatric Neurosciences Pathways 2015

Ridicule and rejection

When a purely scientific advance stands to jeopardize a very powerful interest, rejection can turn threatening.

Such was the case of forensic pathologist Bennet Omalu, a native Nigerian working in the Allegheny County coroner's office. Dr Omalu had no idea just how powerful the National Football League (NFL) was when he published the first diagnosis of chronic traumatic encephalopathy in Neurosurgery.

The NFL immediately mobilized a cadre of physicians on the organization's payroll to attack Dr Omalu's research. Dr Omalu, however, continued publishing, and the NFL continued its attack in kind, very often through physicians with a long history of working with, and for, the NFL.

"I was naive," Dr Omalu told GQ in 2009.[ "There are times I wish I never looked at [former professional NFL player] Mike Webster's brain. It has dragged me into worldly affairs I do not want to be associated with. Human meanness, wickedness, and selfishness. People trying to cover up, to control how information is released. I started this not knowing I was walking into a minefield. That is my only regret."

Even experts without any ties to the NFL initially discounted Dr Omalu's work.

"The credit must go to Bennet Omalu," neuropathologist Peter Davies, of the Albert Einstein College of Medicine in New York, said, "because he first reported this, and nobody believed him, nobody in the field, and I'm included in that. I did not think there was anything there. But when I looked at the stuff, he was absolutely right. I was wrong to be skeptical."

Because of Dr Omalu's persistence, the NFL has been forced to acknowledge chronic traumatic encephalopathy, and the wider sports culture has begun questioning the costs of repeated brain injuries in sports, both professional and recreational.
_____________________________________________________________________________

Incubators are standard equipment in neonatal intensive care units and have become so common that, in many ways, they are emblematic of the care given to premature babies in their first hours and weeks of life.

In the United States, however, for the first decades of their use, the only place infant incubators could be found was at amusement parks and "sideshows" alongside tattooed ladies and sword swallowers.
First pioneered by French obstetrician Stéphane Étienne Tarnier, infant incubators were initially used and refined throughout Europe in the late 19th century.[3] Martin Arthur Couney, who studied under one of Tarnier's assistants, first witnessed an infant incubator at the Berlin Exposition and decided to import them to the United States.

After they were largely rejected by the US medical establishment, Couney established a bank of incubators at Luna Park on Coney Island in New York. From 1903 to the early 1940s, Couney charged visitors 25 cents to view the premies on display, money that was used to pay for the babies' medical care so that parents did not have to.

It has been estimated that Couney treated about 8000 children and saved the lives of 6500 babies during his 4 decades on the Coney Island boardwalk.

In 1939, New York Hospital opened the first official training and research center for premature babies—36 years after Couney debuted his baby incubator in Luna Park. Couney died in 1950 in relative obscurity; however, the widespread adoption of infant incubators is a testament to his courage (and showmanship).
_____________________________________________________________________________

Ignaz Semmelweis may be the best known example of a physician ridiculed for an idea that is now accepted as common sense.

A Hungarian physician working in the maternity ward in Vienna in the mid-19th century, Semmelweis noted that puerperal fever was contagious—students and physicians were performing autopsies and then contaminating new mothers in the maternity ward with what Semmelweis, working prior to the germ theory of disease, termed "cadaverous particles."

Semmelweis advocated that doctors in obstetric clinics disinfect their hands following autopsies; at the clinic in which Semmelweis's hand-washing policy was implemented, the puerperal fever mortality rates dropped 90%, from 18.3% to less than 2%, in fewer than 6 months.

Despite Semmelweis's demonstration of the value of antiseptic techniques, by and large his ideas were rejected by the medical community, with a few notable exceptions. Semmelweis had believed that antiseptic hand washings would be widely adopted and save thousands of lives; when they were not, Semmelweis began publishing a series of vitriolic "open letters" against his critics.

Increasingly isolated and unpredictable, Semmelweis was admitted against his will to a Viennese insane asylum, where he was severely beaten; he died after 2 weeks.

http://www.medscape.com/features/slideshow/medical-breakthroughs?src=wnl_edit_bom_weekly&uac=60196BR&impID=898453&faf=1#page=1

Sunday, November 22, 2015

Why doesn't medical care get better when doctors rest more?

A few days later, the resident caring for the patient neared the teaching hospital’s witching hour: whether or not his work was done, he had to leave at 6 P.M. That’s because, a decade ago, largely in response to widespread concerns that tired residents were making too many errors, the Accreditation Council for Graduate Medical Education enacted nationwide rules that limited the number of consecutive hours residents can work. Five years later, a review of the data suggested that, on average, the rules had failed to make our nation’s teaching hospitals any safer. Proponents of the reforms argued that the rules had neither gone far enough nor been properly enforced. Accordingly, in 2011, first-year residents were limited even more—to sixteen-hour shifts, rather than the thirty hours previously allowed. Training programs scrambled to comply...

The data evaluating the impact of the 2003 reforms suggest that, when it comes to patient safety, little has changed in teaching hospitals. But when it comes to preparing young doctors to manage disease, the training environment has been completely transformed.

For a young doctor, the right course of action isn’t always clear. Acquiring the necessary knowledge and experience requires feedback, which strengthens one’s ability to anticipate how the many variables and small decisions might affect the patient. What’s more, learning how to manage illness demands infinite tweaking; each patient is unique.

But now, residents spend less time directly caring for patients than they once did, and the feedback inherent in the hours once spent with more seasoned physicians has also diminished...
 
The stories of our patients, which we used to own, now come in fits and spurts, passed along via an unending game of telephone. “Anyone know why the heart failure patient’s diuretic was held?” the team leader might ask. “Anyone?” With the resident who made the decision often gone, a mad shuffling of pages invariably ensues, as trainees flip through their lists until someone finds the patient and utters the six saddest words of the shift-limit era: “I don’t know. I’m just covering.” ...
 
Everyone knows how it feels to be tired, and there is nothing easier to count than hours worked or slept. I have lost count of the number of conversations I’ve had with non-doctor friends that have begun, “You do realize sleep deprivation is akin to being drunk?” This sentiment is echoed in a recently published survey of U.S. citizens that found that eighty per cent of people would prefer a different doctor if they knew theirs had been working more than twenty-four hours. This conviction—that a rested doctor who doesn’t know you would be better than a tired doctor who does—fueled the 2003 and 2011 reforms...
 
And although it will be a while before we can really understand the effect of the 2011 reforms, two recently published studies suggest that, right now, both quality of care and quality of education are suffering.
 
One study, led by Sanjay Desai at Johns Hopkins, randomly assigned first-year residents to either a 2003- or 2011-compliant schedule. While those in the 2011 group slept more, they experienced a marked increase in handoffs, and were less satisfied with their education. Equally worrisome, both trainees and nurses perceived a decrease in the quality of care—to such an extent that one of the 2011-compliant schedules was terminated early because of concerns that patient safety was compromised. And another study, comparing first-year residents before and after the 2011 changes, found a statistically significant increase in self-reported medical error...
 
But the other night I had a phone conversation with my mother, who’s also a cardiologist...
 
When she had a cardiac arrest, at home with her boyfriend, she was transferred to my mother’s care. Though the blood flow to her heart had been restored, by the end of the weekend her brain function had not. It was not clear what sort of neurologic recovery, if any, she would have...
 
“Mom,” I said. “It’s 8 P.M. Why on earth are you going to the hospital?”
“I’m going to see my patient,” she said.
“But you have been working nonstop for five days,” I protested. Of course, no one limits the hours of those already in practice, unlike residents. My mom had already worked eighty hours, in all likelihood. And it was only Wednesday.
“Her boyfriend’s driving in,” my mom explained. “He really wants to talk to me.”
And then, without thinking, the words popped right out of my mouth: “But isn’t there someone covering you?”
“I’m her doctor,” my mom said. “I’ve been with her since the beginning. Don’t you think this is important?”
 
Courtesy of a colleague
 

Pediatric arterial ischemic stroke and disability

Pediatric arterial ischemic stroke (AIS) results in long-term impairment, and neuroplasticity does not overcome the disability, a study shows. This emergent condition also results in a high mortality rate. Of 60 prospectively enrolled patients in 2003–2008, 44 were available at 5-year follow-up. Of 44, "63.6% had [neurological impairment]," Mirta Lopez, MD, from the pediatric neurology unit at the Pontifical Catholic University of Chile in Santiago reported here at the XXII World Congress of Neurology (WCN).

She said that "in South America, literature regarding pediatric stroke is scarce" and added that she had not found any studies on long-term outcomes of AIS in children.

This observational study included children aged 30 days to 18 years with AIS confirmed by MRI at her hospital. They were then followed for at least 5 years.

Patients with presumed perinatal cerebrovascular disease, hemorrhagic stroke, transient ischemic attack, watershed infarcts, and hypoxic-ischemic encephalopathy were excluded.

Median patient age was 15 months (range, 5 to 79 months), 43% were less than 1 year old, and 62% were boys. They presented with impairment of consciousness (63.3%), a focal neurologic deficit (55%), seizures (38.3%), and status epilepticus (6.7%), with various risk factors...

During the mean follow-up period of 8.45 years (range, 5.27 to 12.5 years), 9 of the 60 patients had clinical recurrences, 14 died, and 2 were lost to follow-up.
 
Twenty-eight of the 44 evaluable patients at 5 years had neurologic impairment, including 22 with permanent motor deficits (10 quadriparesis, 9 hemiparesis, 3 dystonic), 18 with epilepsy, and 6 with refractory epilepsy...

Dr Lopez and colleagues identified several radiologic predictors of long-term impairment and of death. Having multiple infarcts was an especially strong predictor of refractory epilepsy...

The results of this study are generally in line with those of previous studies, which found that 63% to 94% of patients had permanent neurologic disabilities and a recurrence rate of 10% to 30%.
However, the mortality rate in this study was 23.3% (14 of 60), whereas it has typically been around 12% in studies from the United States. Dr Lopez ascribed the higher mortality she saw to an elevated frequency of congenital heart diseases in her cohort.

She concluded that "in spite of neural plasticity, most children who have suffered an AIS have persistent disability."

Session chairman Samuel Wiebe, MD, professor of neurology at the University of Calgary, Alberta, Canada, said this "interesting study" applies to a very specific population.
"This is a referral center that specializes in cardiac surgery, and the children had an MRI, so there could be children that don't have an MRI that have a different type of outcome and so forth," he commented to Medscape Medical News.

He noted that the study sheds light on the importance of a specific type of stroke in neonates that is not necessarily associated with arteriopathy.

He said he found it remarkable that such a large proportion of the children had a bad outcome.
"Despite the plasticity of the nervous system in the very, very young human, these effects are devastating to a large proportion of them," Dr Wiebe noted. "That is probably an important aspect to consider as well."

XXII World Congress of Neurology (WCN). Abstract 427. Presented November 2, 2015.

http://www.medscape.com/viewarticle/854589?nlid=91848_3404&src=wnl_edit_medn_neur&uac=60196BR&spon=26&impID=896175&faf=1

Friday, November 20, 2015

Huntington's hope

Gene silencing and editing techniques aimed at modifying the mutant huntingtin gene (HTT) to reduce levels of the protein promise to change the landscape for patients with Huntington's disease (HD), according to several reports presented at the Society for Neuroscience annual meeting here in October...

Scientists at the University of British Columbia's Centre for Molecular Medicine and Therapeutics (CMMT) identified eight of the most common genetic variations on the HTT gene associated with HD and tested specialized antisense oligonucleotides (ASOs) in blood cells from HD patients to assess whether the drugs can silence, or turn off, the mutated gene and reduce levels of the toxic huntingtin protein. The drugs work by binding to the messenger RNA and inducing degradation of the transcript, preventing synthesis of the mutant protein...

Dr. Hayden's team has evaluated ASOs that target one of the HD SNPs they identified, and they are now using a potent and well tolerated ASO in animals to see whether it is effective at reducing the mutant huntingtin protein. They are developing a panel of ASOs targeting HD SNPs specific to the three most common HD HTT haplotypes.

Lowering mutant huntingtin in animal models of HD has proven effective at reducing the motor and behavioral symptoms, as well as the neuropathology observed in the brain. RNA interference methods are also being developed by other groups to reduce the huntingtin protein...

The first clinical trial using a non-selective HTT silencing approach (targeting the wild-type and mutant genes) is now underway...

The drug, ISIS-HTTRx, is injected into the spinal fluid...

We designed ISIS-HTTRx to target the huntingtin gene and reduce the production of huntingtin protein,” said C. Frank Bennett, PhD, senior vice president of research at Isis Pharmaceuticals...

Scientists at the Institute for Regenerative Cures and the Genome Center at the University of California, Davis, are using transcription-like effectors (TALEs) in primary human HD fibroblasts and neurons to see if they can reduce mutant huntingtin. TALEs are DNA-binding molecules that can be designed to target single nucleotide polymorphisms in the mutant allele. The TALE molecules either cause a CAG collapse in the expanded mutant allele or provide transcriptional repression of the mutant gene...

The TALE recognizes sequences in DNA and makes a double-stranded cut, which would collapse the CAG length down to a non-disease stage, or, when using KRAB, cause transcriptional repression the mutant allele...

The research team conducted real-time quantitative assays to measure how much transcription of the mutated gene occurred. The technique lowered the expression of the mutant gene to near-normal levels. The expression of the healthy gene was not affected by the treatments...

Nicolas Merienne, PhD, and his colleagues in the laboratory of cellular and molecular neurotherapies at Lausanne University Hospital in Switzerland, used the gene editing technology, referred to as clustered regularly interspaced short palindromic repeats (CRISPR), to test its power to edit out the mutant gene and alter the reading frame of the HTT gene that would lead to a loss of mutant HTT expression...

“We've only done a local proof of principle in the striatum,” Dr. Merienne said. “We have not looked for behavioral changes or functional recovery yet.” He added that the researchers are now evaluating the impact of allele or non-allele-specific mutant HTT editing in human neurons cultured from HD patients.

“CRISPR is by far the most efficient system,” said Nicole Déglon, PhD, head of the laboratory at Lausanne University Hospital. “We are still trying to identify the efficient and safe system to use in humans. One of the major concerns is treating enough cells in the brain to have a therapeutic effect. We have to be absolutely sure that we are not doing anything else off of our target gene.”...

Christopher Ross, MD, PhD, a professor of psychiatry, neurology, pharmacology, and neuroscience at Johns Hopkins University School of Medicine and director of the Baltimore Huntington's Disease Center at Hopkins, said that the nature of HD — it is a triplet repeat expansion — is that it is hard to get an intervention to the mutated allele without affecting the wild-type allele.

“One strategy is to target other parts of the HD message whose sequence is specific to the mutant allele,” Dr. Ross said. “This strategy is attempting to correct the gene defect, and another difficulty is that you need to get every cell, or at least a significant number of them. Delivery of these therapeutic agents into relevant areas of the brain is very challenging. You use these technologies to edit the mutant gene, and thereby disrupt its ability to transcribe mRNA to make mutant protein...

Willeke van Roon-Mom, PhD, an assistant professor at Leiden University Medical Center in the Netherlands, also studies transcriptional changes in both cell models of HD and HD patients. She also studies possible therapeutic treatments, including small antibodies specific for the huntingtin protein and ASOs.

“These approaches make a lot of sense,” she said, commenting on the studies, noting that these approaches could reduce up to 50 percent of the mutant huntingtin protein. “Scientists can design a drug that only targets the sequence in which they are interested. I think this strategy will work. But you always have patients who don't have the common SNPs, so other strategies are needed too.”

http://journals.lww.com/neurotodayonline/Fulltext/2015/11190/News_from_the_Society_for_Neuroscience_Annual.6.aspx

Cute seizures

I wrote: A 14 months old girl with mosaic trisomy 12p has an EEG obtained to evaluate paroxysmal behaviors. During an extended duration videoEEG, she had seizures manifest as a quick shrug of the shoulders and, perhaps, ocular supraversion associated with a brief generalized paroxysmal discharge. These created no obvious interruption. I have to say the seizures were cute. With a sigh, I initiated a trial of levetiracetam therapy. I remember a 5 1/2 year old boy whose EEG and videoEEG showed generalized bursts of paroxysmal activity of 1-4 seconds, associated with a brief pursing of the lips, which I told his mother were the cutest seizures I had seen. He was treated with valproate, which seemed to cause adverse behavior, and subsequently lamotrigine. Later, while already receiving antiseizure pharmacotherapy, he had a generalized tonic-clonic seizure at a time of intercurrent illness. Indeed, do all seizures, particularly cute ones, need to treated? If my patients' parents, like I, had found their behavior cute and resisted antiseizure pharmacotherapy, how remiss would I be to go along with them? Would non-treatment truly jeopardize their development? Certainly, these could evolve into more ugly seizures, but that happened in my second patient despite the institution of pharmacotherapy, so there is obviously no guarantee. Could treatment be deferred until seizures became ugly? Are there seizures that can be acknowledged and, perhaps, admired?

(Correspondents' replies are uncorrected)

A correspondent replied: Galen Breningstall asks a very interesting question regarding the philosophical (dare I even say spiritual) significance of fairly minor seizure activity. Are we so convinced by the animal data that all seizure activity is deleterious to the developing brain that we need to wage a pharmacological war against every behavior that is accompanied by paroxysmal EEG activity? Seizures have been demonized in so many cultures that we want to make them all go away, even when that is not necesssarily the case (as in the Hmong culture described in "The Spirit Catches You and You Fall Down" by Anne Fadiman). Are we sure of the reasons why we want to do this?
I don't know whether the idea that seizures are "cute" should be a factor (maybe that plays into our own culture-driven ideas about desirable versus undesirable appearances). But at least it may be worth talking openly to parents about the risks and benefits of treatment versus nontreatment of these sort of fairly minor epileptiform behaviors, and not being too judgmental if they choose a nontraditional approach.
It is a good question that deserves serious discussion.
 
Another correspndent replied: Galen Breningstall asks a very interesting question regarding the philosophical (dare I even say spiritual) significance of fairly minor seizureIndeed we need to reexamine the probably secular notion that epilepsy even if involves very few not prolonged seizures need to be treated vigorously forever. Two strong concepts motivate that point of view:seizures damage the brain (neurodegeneration another strongly established concept) and they can kill. The explosion of new knowledge on cytokines and other factors and the genetic of the two hundred synaptic proteins necessitate revision of the old ideas but will be complex and therefore not attractive to granting agencies.
At a less discouraging level one might fruitfully discuss how to balance the interests of patients, families and society.
 
A third correspondent replied:  There is always a risk benefit balance in using antiepileptic drugs and many believe in most cases the benefits of controlling seiures balance out the risk from AED, However the difficulty we have is often proving that statment in an individual patient. Though EEG,S and its interpretaions are improving all the time we do not have a objective indisputable parameter of improvement like say blood sugar in daibetes or measurment of blood pressure.This becomes particulary difficult in those with only ocassional seizures.WE therfore have to rely on statistics   changes that left untreated these seizures could worsen
1)What are the changes that left untreated these seizures could worsen
2)Is there any risk of the abnrormal electrical discharge itself causing damage ?
3)Is there any risk at all of status/SUDEP etc in these patients?
 
I remember there were quite a few in one of the AES meetings I attented who felt even bemnign epilepsy with centrotemproal spikes should be left alone
 
It would be an interesting issue for discussion and then there are "pleasurable seizures"oh well
 
 
 
 
 

Thursday, November 19, 2015

The place of stories

Recently, Dr. Peter Kramer published an intriguing, well-written, but poorly reasoned and potentially dangerous "thought piece" in The New York Times. His article, "Why Doctors Need Stories," contains several logical flaws and erroneous arguments, but the overarching concept is a classic "straw man" argument.

He creates a false and highly misleading notion of what "evidence-based medicine" (EBM) is and then proceeds with a screed against EBM in order to extol the virtue of the anecdote. This sort of argument works particularly well when the reader has little or no knowledge of the term being misrepresented, so I expect it's been quite effective even with the generally well-informed Times readership, who wouldn't be expected to know what EBM is.

So let's start with what Kramer says about EBM in his piece. He notes that his preferred approach, "giving weight to the combination of doctors' experience and biological plausibility, stands somewhat in conflict with the principles of evidence-based medicine. The [EBM] movement's manifesto, published in the Journal of the American Medical Association in 1992, proclaimed a new era that would see near-exclusive reliance on systematic clinical research -- the direct assessment of treatments in patients."

Kramer allows himself some wiggle room by saying "somewhat" and adding "near" to "exclusive reliance," but the point is crystal clear: these doctrinaire EBMers, manifesto in hand, are preventing us warm and caring docs from talking with our patients, forcing us into a mindless and soulless practice of cookbook medicine wherein we follow protocols and algorithms and ignore the heartfelt pleas of our patients seeking succor and support. If only doctors were trained to listen to their patients, to understand the power of stories, we'd all be happier and healthier...

Looking at this "manifesto," I found it almost amusing to see what the authors wrote 22 years ago in describing how wrong-headed doctors make false arguments against EBM: "Misinterpretation 1. -- Evidence-based medicine ignores clinical experience and clinical intuition." (Straw man, anyone?)
Now let's look at what EBM really is. As defined nearly 20 years ago by David Sackett, one of the founders of this discipline: "Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research."

Patients' stories -- case histories -- are evidence. All of the EBM "manifestos" acknowledge that, and case reports have always been part of the EBM landscape. (Indeed, my own first publication was a case report.) But there is an important caveat: case studies (and patients' stories) are weaker evidence than carefully designed and conducted (and appropriately interpreted) research studies. There is a hierarchy of evidence, and case reports are at the lowest level of that hierarchy. There are excellent reasons for this, but that's a separate discussion...

A more serious critique from a leading thinker in clinical epidemiology is provided in a frequently downloaded paper from the Public Library of Science. In a provocatively essay titled "Why Most Published Research Findings Are False," John Ioannidis argues that small sample and effect sizes, large numbers of tested relationships, limitations in study designs, and financial and other conflicts of interest all contribute to a greater likelihood of a study's conclusions being false (see Research reproducibility 8/27/15). Given these factors, a positive predictive value greater than 50% is difficult to obtain, he added. This, of course, doesn't suggest that stories have primacy over evidence; rather, that evidence requires thoughtful interpretation to reach reasonable conclusions...

The persuasive power of the piece is enhanced by the image of the lone wolf crying out for justice in an unjust world: "I have long felt isolated in this position, embracing stories." Nice image, but a quick look at the world around him would have shown Dr. Kramer that he is not alone. Indeed, the growth of what has come to be known as "narrative medicine" began in the 1990s, paralleling (and perhaps partly in response to) the development of EBM. Now, in my opinion, the valuing of stories over evidence is highly dangerous, and if you're looking for acolytes rather than scientists, you're more likely to find them preaching narrative medicine than practicing EBM... . But look at me: Kramer has got me mirroring his false dichotomy.

Any good doctor knows that both listening to stories (in the context of clinical experience and good judgment) and applying research studies (judiciously and competently) are required to practice medicine. Caring for patients using one without the other is a fool's errand. (And by the way: my medical school, like most medical schools, puts a lot of effort into teaching communication skills -- including through "narrative medicine" -- to its students.) Blending the two approaches effectively and seamlessly isn't easy, but the goal of medical education -- and doctoring -- is to strike the right balance.

http://www.medpagetoday.com/Blogs/Doctor'sTablet/48593

Conjoined twins

A set of conjoined twins scheduled for delivery on Monday in Augusta, Georgia, can be seen in a sonogram facing one another as though embracing. The sonogram, which was taken at 15 weeks, shows the twin boys who are joined at the heart.

The boys’ mother, Brittany Crofton, 26, said the image was a rare sight.

"I didn't see, 'oh... conjoined [twins].' I didn't think about that. I saw two little babies," Crafton told Fox 5 Atlanta when she saw her first sonogram.

There is a good prognosis for survival, doctors at Georgia Regents Medical Center said. The boys share a heart and liver, have clubfoot and a dislocated hip.

Surgical separation is only possible if one of the babies receives a heart from a donor.

“What makes this case special, is that the heart the twins share is quite normal and has been functioning very well for them. So, we believe it will continue to function well after the delivery,” Dr. Paul Browne of the maternal-fetal medicine department at Georgia Regents University and Health System said in a news release.

http://www.foxnews.com/health/2015/11/05/sonogram-shows-conjoined-twins-embracing.html

The Georgia hospital where conjoined twins were born last week released a statement Thursday confirming that the newborns had died.

Chandler and Chance Crafton, who shared a heart and liver, suffered from clubfoot and had a dislocated hip, passed away Wednesday due to “multiple complex medical complications,” Georgia Regents Medical Center in Augusta said, according to Fox 5 Atlanta.

Their story had gone viral after their mother, 26-year-old Brittany Crafton, shared a sonogram photo of her sons that showed them embracing.

“I didn’t see, ‘oh … conjoined [twins].’ I didn’t think about that. I saw two little babies,” she told the news station at the time. Seeing them embrace in the second ultrasound ultimately drove her to carry the twins to full term.

“How could you do something to two little babies, just looking like they’re hugging each other?” she said. After their birth, she said her faith had helped her during the pregnancy and delivery.

Doctors had predicted that the boys had a good chance for survival, though the only chance for separation would have been if one received a donor heart. They were delivered via caesarian section Monday and had been listed in critical condition. The hospital said Crafton remains in good condition at this time, Fox 5 Atlanta reported.

http://www.foxnews.com/health/2015/11/12/conjoined-twins-whose-sonogram-embrace-went-viral-die-hospital-says.html?intcmp=ob_article_footer_text&intcmp=obnetwork