Wednesday, July 31, 2019

Child abuse expert witness

A Boston hospital has notified the Massachusetts medical board that it has restricted the work of a world-renowned endocrinologist criticized for espousing controversial theories as an expert witness for people accused of child abuse.

The action against Dr. Michael Holick is cited on his profile page on the board’s website under “health care facility discipline.” The listing is intended to alert members of the public who visit the site that Boston Medical Center, where Holick practices, has restricted his rights or privileges.

Last September, ProPublica and The New Yorker reported that Holick had testified in hundreds of child abuse cases worldwide and almost always blamed broken bones and other injuries on a rare genetic disorder. At the time, Boston Medical Center said that it had barred Holick from treating or evaluating children under age 13 beginning in May 2017. But Holick continued evaluating children in suspected abuse cases as part of an approved research project, and it now turns out that the discipline was not reported to the board until this past February.

A hospital spokesman, in an email last week, wrote that the filing with the medical board “is consistent with” the information it provided ProPublica last year. The spokesman, David Kibbe, also indicated that Holick is still allowed to evaluate children who participate in his research project.

The medical board requires hospitals to report disciplinary actions within 30 days of taking them. When asked about the 21-month gap between the hospital barring Holick from treating children and the report to the medical board, Kibbe responded, “We complied with our reporting obligations.” He offered no further explanation.

A spokesman for the Massachusetts Board of Registration in Medicine said the details of the hospital action against Holick are confidential.

Holick, who did not respond to calls or emails seeking comment for this story, is best known in medical research circles for pioneering work related to vitamin D. He discovered the active ingredient in the vitamin, leading to treatments for bone disease in kidney patients. He also figured out that orange juice helps the body absorb vitamin D, a finding that led to the U.S. Food and Drug Administration approving vitamin D-fortified orange juice. 

Earlier this decade, Holick began working as an expert witness in child abuse cases in the U.S. and abroad. He has consulted or testified in more than 300 cases, always on behalf of the accused. As of last September, he had never concluded that a child was abused, and he had almost always attributed the injuries to Hypermobile Ehlers-Danlos syndrome, a condition that affects the connective tissues of the skin, bones and joints and has been linked to bone fragility in adults.

The ProPublica-New Yorker article focused on a social services investigation in South Carolina that found that 3-week-old twins had allegedly been abused. The parents consulted Holick, who concluded that both babies had Ehlers-Danlos, and that fractures attributed to abuse could have been caused by bone fragility associated with the genetic condition. Nearly eight months later, one of the twins suffered a severe brain injury and the child’s father was charged with abuse to inflict great bodily injury upon a child. That criminal case is pending.

“Thousands, if not tens of thousands,” of parents worldwide have been falsely accused of fracturing their children’s bones, Holick told ProPublica last year. “It’s just terrible. I feel so sorry for these parents.”

His work has drawn rebukes from other physicians who specialize in treating patients with the genetic disorder. They cite a lack of research supporting Holick’s view that Ehlers-Danlos can cause broken bones in very young children. Holick has also been criticized for diagnosing the condition in children he didn’t examine in person.

Boston Medical Center is the teaching hospital affiliated with Boston University School of Medicine, where Holick is a longtime faculty member. A spokeswoman for the medical school said Holick remains on the faculty.

Boston University has defended Holick’s right to testify about his Ehlers-Danlos theory in court. The dean of the medical school, Karen Antman, in a letter to another physician critical of Holick, wrote that she didn’t need to know the details of his expert defense work. “As a member of the Boston University School of Medicine faculty, academic freedom allows Dr. Holick to espouse his views without censorship from the University,” she wrote.

In the past seven years, Holick said, he has consulted or testified as an expert witness in more than 300 child-abuse cases throughout the U.S. as well as the United Kingdom, New Zealand, Australia, Germany and Canada. In almost every case, he has made the same finding: instead of blaming any injuries on abuse, he has diagnosed the child with a rare genetic disorder, Hypermobile Ehlers-Danlos syndrome, a condition that affects the connective tissues of the skin, bones and joints. A handful of studies on adults have linked EDS to bone fragility, and Holick argues that children with the disorder have weaker bones, which can fracture from normal handling. So far, his theory is not supported by the scientific literature, but Holick is convinced that “thousands, if not tens of thousands,” of parents worldwide have been falsely accused of fracturing their children’s bones. “It’s just terrible,” he told me. “I feel so sorry for these parents.”

In all the cases he has worked on, Holick has never concluded that a child was being abused. On the rare occasions when he didn’t diagnose EDS, he attributed the bone fractures to rickets or vitamin D deficiency. Many geneticists and bone specialists find it troubling that he diagnoses EDS in nearly 100 percent of the cases he examines. According to the National Institutes of Health, EDS affects, at the most, 0.02 percent of people worldwide. The rate at which Holick diagnoses the disorder “doesn’t fall into the mathematical probability of chance,” Brad Tinkle, a clinical geneticist at Peyton Manning Children’s Hospital, in Indianapolis, said. Holick retorts that his clients don’t come to him by chance; parents contact him after doing their own research and realizing that they or their children have symptoms of EDS. He adds that he hasn’t seen a single actual abuser pretending to have EDS and contacting him in search of a “get out of jail free” card.

Holick regularly diagnoses children with EDS without seeing them in person. “I already know on the phone they have EDS,” he said, adding that he questions the parents about potential symptoms. “I almost don’t have to ask. I know the answer.”...

In 2017, he co-published an article about his EDS work in the little-known journal Dermato-Endocrinology, where he is an associate editor. (He was unable to get more prestigious medical journals to publish the study.) In the study, Holick examined the cases of 72 children who the authorities believed had been abused. He diagnosed 67 of them with EDS. In a third of the cases, he based his diagnosis on physical exams of relatives of the children, not the children themselves.

“How can you do that without an exam?” Brendan Lee, the chair of the Molecular and Human Genetics department at Baylor College of Medicine and the director of the Skeletal Dysplasia Clinic at Texas Children’s Hospital, said. He added that hypermobile EDS “is a diagnosis that is made based on a constellation of clinical findings, which you have to do by examination and history.”

Lee and several other experts said that hypermobile EDS typically cannot be diagnosed in children younger than five. Because infants are usually very flexible, they will likely score high on elements of the test given to older patients to determine hyperflexibility, a key aspect of EDS. Also, symptoms of the condition do not usually manifest until later in childhood, or even adulthood. “I would not be comfortable, ever, telling a parent that an infant has (hypermobile) EDS,” Lee said.

There are four studies that Holick consistently cites to support his conclusions. I asked Rodney Grahame, the author of two of those studies and a former president of the British Society for Rheumatology, whether he finds Holick’s theory of a link between EDS and bone fractures in infants to be reasonable. “Not at all,” Grahame responded in an e-mail. “It may ‘stand to reason’, but it is not supported by published scientific research. In adults, other factors are at play including ageing and the menopause, alcohol, smoking which are factors associated with osteoporosis that are not present in infants.”

Cristina Eller Vainicher, the lead author on another paper that Holick frequently cites, said that she can’t entirely discount his thesis, because some studies have suggested that a subset of EDS patients experience fragility fractures during childhood. Still, she wrote in an e-mail, “This does not mean that we could state all children with hypermobile EDS are at high risk of fractures.”

Holick’s credibility as an expert witness is buttressed by a formidable scientific resume, mostly related to his work on vitamin D...

Holick, who is now 72, gives talks around the world on the importance of vitamin D. He was billed as a “legend” at the most recent annual meeting of the American Association of Clinical Endocrinologists. He has published more than 500 articles in peer-reviewed journals and more than 200 reviews and book chapters. Since 2011, other scientists have cited him almost 110,000 times, making him one of the most frequently cited researchers in the world...

But Holick’s career has also been dogged by controversy. He came under fire for recommending the use of tanning beds based on research he’d done partly with funding from a foundation established by the Indoor Tanning Association, a relationship that I reported on in The Wall Street Journal. He also published a book called “The UV Advantage,” in which he urged people to soak up unfiltered sun two or three times a week. “Do not be afraid,” Holick wrote. “You are not going to die just because you go out in the sun.”...

“It seems so intuitively obvious,” he told me. “No one ever connected the dots. No one in the pediatric or child-abuse community ever made an effort to find other potential mitigating circumstances to explain these fractures, other than a rush to judgment.”

He testified in court on the family’s behalf, and the baby was returned to his parents. Word of Holick’s success began to spread. He now receives pleas for help from parents accused of abuse on almost a daily basis. Holick said he doesn’t charge for his services, though he does solicit donations for his Ehlers-Danlos research. About a quarter of the funding for his EDS research in the past four years — about $125,000 — has come from two families who had abuse charges dropped after Holick intervened in their cases, he said.

Holick is one of the most prominent and sought-after expert witnesses for the defense in child-abuse cases. He told me that about half the parents he assists end up with a positive outcome, such as getting their children back or having abuse charges dismissed. However, he has sometimes claimed a much higher success rate. “Before I started testifying in these court cases on behalf of the family 100% of these cases had been won by the prosecution,” he wrote as part of an unsuccessful plea to the editor of a medical journal to publish his study on EDS and child abuse. “Now that I am testifying on behalf of the family 90% of the cases have been won by the parents and their children have been returned to them without further incident.”...

“I truly believe you could be an angel put on this earth to show the justice and glory of the almighty,” a father from New Hampshire wrote to Holick in 2016. “The good you’re doing on this earth is amazing, incredible, inspiring, loving, noble, and even incomprehensible.”...

The mutual enmity between Holick and abuse experts at children’s hospitals is hard to overstate. Lori Frasier, the head of the Division of Child Abuse Pediatrics at Penn State Hershey Medical Center, started encountering Holick in court several years ago. Frasier told me that she was struck by Holick’s arrogance. “Maybe he is feeling like he is really, really smart and seeing something the rest of us can’t see,” she said. He might view himself as “a Copernicus of this century, or Galileo, fighting the status quo.”

Holick describes specialists like Frasier as zealots who, because of their training, see abuse behind nearly every mysterious injury that comes through the hospital door. “I naively assumed people want to be educated,” Holick said. “They don’t. They are child-abuse experts. They have to know.”

Unlike Holick, Frasier serves as an expert witness for both prosecutors and defendants, and recently testified in Nevada for a father accused of child abuse. (The father was acquitted in the case.) In May 2016, Holick appeared on a Philadelphia television station, saying that a baby’s injuries were likely the result of EDS and a vitamin D deficiency, not child abuse. Two days later, Frasier sent a concerned e-mail to Karen Antman, the dean of Boston University Medical School. “Dr. Holick makes statements regarding the infant’s medical condition that have no evidence base,” she wrote, noting that other experts had ruled out EDS in the case, and that even if the boy did have the condition there was no evidence it would make his bones fragile. “He is bringing the reputation of Boston University into disrepute.”

Antman replied with a defense of Holick and said she didn’t need to know the particulars of his expert work. “As a private citizen and a physician, Dr. Holick is entitled to provide consultative services and testify as an expert witness,” she wrote.  “As a member of the Boston University School of Medicine faculty, academic freedom allows Dr. Holick to espouse his views without censorship from the University.”...

Seven months after Frasier complained to Holick’s dean, a pediatric geneticist at the Children’s Hospital at Albany Medical Center also raised concerns about him with B.U. Natasha Shur wrote in an e-mail to Holick’s department head, Alan Farwell, that Holick’s expert findings lacked scientific support. “I hope that you are interested in considering these issues, and the effect of BU and its involvement,” she wrote.’’

Nevertheless, she finds Holick’s assertions alarming. When she takes the medical histories of patients with EDS, she told me, they don’t mention frequent fractures or brittle bones. “My patients are the first ones to state, ‘I never fractured as a baby,’” she said. “They have had to deal with joint dislocations, joint pain, but as a whole have not had to deal with unexplained fractures.”...

“Academic freedom is not just about saying what you want,” John Leventhal, the medical director of the Yale-New Haven Children’s Hospital Child Abuse Program, said. In an article for the Journal of the American Medical Association last year, Leventhal and his co-authors said that academic medical centers should take some responsibility for the testimony of physicians who promote “flawed theories” in child-abuse cases. “If medical faculty at these institutions testified under oath that smoking did not cause cancer or that HIV did not cause AIDS, would such testimony be tolerated?” he wrote...

It wasn’t until later, after reviewing relevant literature in the field, that Sege determined that he could not validate the link between EDS and infant bone fractures. “I believe this is his firmly held belief,” Sege, who is now a professor at the Tufts University School of Medicine, said of Holick. “It is not backed by evidence.”

Still, Sege said, one comment of Holick’s unnerved him: Holick told him that he doesn’t recommend that parents in potential abuse cases test for osteogenesis imperfecta, the disease known to cause injuries that look as though they might be the result of abuse. Holick acknowledges advising against testing for the disorder. “It’s incredibly rare,” he said, and the test “will come back negative,” adding to the impression that “you are a child abuser.”

“That is a real red flag,” Sege said. “I am a doctor. I test for all things out there before I go to the thing that is my invention. I test for everything I can. It is alarming to tell someone not to get a test because it might impact your court case.”

In May 2017, Boston Medical Center banned Holick from using “its facilities to treat or evaluate patients under the age of thirteen for any reason,” the hospital said in a statement for this article. It said that its “medical leadership” made the decision, but didn’t explain why. Holick said that complaints about his child-abuse work prompted the edict...

This past January, Holick received a phone call so unsettling that he doesn’t even remember who was on the other end. The caller said that the child of a family Holick helped in an abuse case was in the hospital with a serious brain injury, and the father had been arrested.

“Look what you’ve done,” the caller said, according to Holick.

The child was one of Jenn and Robbie Ray’s twins. Officials in South Carolina had agreed to a plan to gradually reunite the family. They‘d had three weekends of unsupervised visits. Now the local newspaper featured a mug shot of Robbie Ray in orange prison garb...

But I believe that what likely happened is just like he was stating: that he was innocently swinging his child in the swing and bumped the head. Unfortunately, the pediatrician and or emergency doctor didn’t actually connect dots and didn’t realize that, if that infant or child has EDS, and if they’re having trauma, they should be more concerned about a brain bleed and not to have sent that child home.”

The explanation is, in many ways, typical of how Holick views these cases. He is quick to declare that a trivial accident has resulted in injuries that can be explained by his diagnosis, that the child has received incompetent medical care from less knowledgeable doctors and that the authorities have rushed to judgment.

Holick’s description of the incident, however, is largely inaccurate. The girl was 8 months old, not 2 years. Robbie wasn’t “innocently swinging his child in the swing.” By his account, he had strapped the baby into a motorized Fisher-Price swing, with the seat about a foot off the floor, while he sat on the couch and fed the other child. He didn’t drive the baby to the hospital; he called 911, and an ambulance took her. In a recording of that call, Robbie seems to be sobbing as he tries to awaken his unconscious daughter. “What’s wrong with her?” he asks the 911 operator. “What happened?”...

Nor could Holick’s comment that she “bumped her head” explain the damage to the rest of her body. Her right leg was broken near the thigh. A photograph from the hospital shows the infant lying on her back, with one eye swollen shut and bruises on her right eye and nose. There appears to be dried blood on her left hand.

Holick said that he called Jenn Ray to find out what happened, and that he’s confident the latest injuries weren’t caused by abuse, either, but were another complication of EDS.

Holick will be watching the Ray case from Boston. Mistakes happen in medicine, but he realizes that one high-profile misstep on his part could greatly damage his credibility.

“I’m very, very concerned this could upend this whole activity, if even one of the cases of the hundreds turns out to be a child-abuse case,” he said. But he acknowledged the possibility that the case might not turn out as he would like. “You know, these types of things are going to happen,” he said.

In another conversation, he reflected on the impact of his crusade to reunite families divided by child-abuse allegations. “To date,” he said, “almost all of the kids I helped return to parents are happy and well.”

Courtesy of a colleague

Tuesday, July 30, 2019

Doctors In U.S. use CRISPR tool to treat patient with genetic disorder

For the first time, doctors in the U.S. have used the powerful gene-editing technique CRISPR to try to treat a patient with a genetic disorder.

"It is just amazing how far things have come," says Victoria Gray, 34, of Forest, Miss. "It is wonderful," she told NPR in an exclusive interview after undergoing the landmark treatment for sickle cell disease.

Gray is the first patient ever to be publicly identified as being involved in a study testing the use of CRISPR for a genetic disease.

"I always had hoped that something will come along," she says from a hospital bed at the Sarah Cannon Research Institute in Nashville, Tenn., where she received an infusion of billions of genetically modified cells. "It's a good time to get healed."

But it probably will take months, if not years, of careful monitoring of Gray and other patients before doctors know whether the treatment is safe and how well it might be helping patients…

For the study, doctors are using cells taken from patients' own bone marrow that have been genetically modified with CRISPR to make them produce a protein that is usually only made by fetuses and by babies for a short time following birth.

The hope is this protein will compensate for the defective protein that causes sickle cell disease and will enable patients to live normally for the rest of their lives.

"It's exciting to see that we might be on the cusp of a highly effective therapy for patients with sickle cell," says Dr. David Altshuler, executive vice president, global research and chief scientific officer at Vertex Pharmaceuticals in Boston. Vertex is conducting the study with CRISPR Therapeutics of Cambridge, Mass.

CRISPR Therapeutics announced the treatment of the first volunteer on Monday but did not name the patient. However, NPR got exclusive access to Gray…

"This is a very big deal," agrees Dr. Haydar Frangoul, medical director of pediatric hematology/oncology at the institute where Gray volunteered. "This could benefit many patients."

Frangoul's center, Sarah Cannon, is conducting the study at HCA Healthcare's TriStar Centennial Medical Center in Nashville, which is one of eight sites recruiting patients for the research in the United States, Canada and Europe. Up to 45 patients ages 18 to 35 will eventually be enrolled.

Other doctors, scientists and bioethicists are also encouraged.

"This is an exciting moment in medicine. CRISPR promises the capacity to alter the human genome and to begin to directly address genetic diseases," says Laurie Zoloth, a bioethicist at the University of Chicago.

But Zoloth is also cautious. She worries that this and other studies starting up using CRISPR haven't gone through an extra layer of scrutiny by a panel of outside experts assembled by the National Institutes of Health.

"This a brand-new technology," Zoloth says. "It seems to work really well in animals and really well in culture dishes. It's completely unknown how it works in actual human beings. So there are a lot of unknowns. It might make you sicker."

Frangoul acknowledges there are always risks with experimental treatments. But he says the research will go very slowly and carefully with close review by the Food and Drug Administration and other advisory panels.

"We are very cautious about how we do this trial in a very systematic way to monitor the patients carefully for any complications related to the therapy," he says…

Some patients can get bone marrow transplants, but those procedures are grueling and can be dangerous if the immune system cells produced by the transplanted bone marrow attack their bodies. And most sickle cell patients either don't have or don't find a suitable donor.

"It's real hard," Gray says. "It was just my religion that just kept me going."

When she was considering a bone marrow transplant, she heard about the CRISPR trial and jumped at the chance to volunteer.

"I always knew something had to come along and that God had something important in store for me," Gray says. "It felt like this was meant to be. It was kinda fate. That was an amazing feeling."

CRISPR enables scientists to make very precise changes in DNA, raising hopes it will lead to new ways to prevent and treat many diseases.

"CRISPR technology has a lot of potential use in the future, not only in blood disorders," Frangoul says.

Doctors have already started using it to try treat cancer, mostly in China. At least two patients in the U.S. have been treated for cancer, in a study at the University of Pennsylvania in Philadelphia.

Later this year, doctors in Boston are planning to use CRISPR to edit cells in patients' retinas, in hopes of restoring vision in patients with an inherited form of blindness.

The companies sponsoring the sickle cell study announced earlier this year that they had used CRISPR to treat the first patient with a similar blood disorder, beta thalassemia, in Germany.

On Monday, CRISPR Therapeutics also revealed the first hint that the approach might be working for beta thalassemia. The beta thalassemia patient's edited cells have started functioning in the bone marrow, according to the company's press release.

Moreover, that patient has not required a blood transfusion for more than four months, the company says. Beta thalassemia patients normally require regular transfusions to treat their condition.

Beta thalassemia and sickle cell disease are both caused by genetic defects that cause problems with a protein called hemoglobin. Healthy red blood cells use hemoglobin to carry oxygen throughout the body…

Beta thalassemia and sickle cell disease are both caused by genetic defects that cause problems with a protein called hemoglobin. Healthy red blood cells use hemoglobin to carry oxygen throughout the body.

Sickle cell patients' red blood cells carry defective hemoglobin that deform the cells and don't transport enough oxygen. The hope is that another form of hemoglobin, known as fetal hemoglobin, will compensate for the defective protein.

Fetal hemoglobin is produced by fetuses in the womb to provide oxygen. In most people, fetal hemoglobin production stops shortly after birth.

"Once a baby is born, a switch will flip on," Frangoul says. "It's a gene that tells the red blood cell — the bone marrow cells that produce red cells — to stop making fetal hemoglobin."

This CRISPR treatment starts with doctors extracting bone marrow cells from patients' blood. Company scientists then use CRISPR to edit a gene in the cells to make the cells produce fetal hemoglobin.

The patients then undergo the same kind of grueling chemotherapy administered as part of a standard bone marrow transplant. That wipes out the existing cells that are carrying the genetic defect. But instead of receiving new cells from a donor, the patients get billions of their own cells that have been edited with CRISPR.

The hope is that it will provide a treatment option for all patients, including those who can't find a matched donor. The approach hopefully will be safer because the cells come from patients' own bone marrow. So they shouldn't attack patients' bodies, Frangoul says.

"This opens the door for many patients to potentially be treated and to have their disease modified to be mild" and to avoid the "horrible, horrible long-term side effects of sickle cell disease," he says.

Haploinsufficiency of USP7

Fountain MD, Oleson DS, Rech ME, Segebrecht L, Hunter JV, McCarthy JM, Lupo PJ, Holtgrewe M, Moran R, Rosenfeld JA, Isidor B, Le Caignec C, Saenz MS, Pedersen RC, Morgan TM, Pfotenhauer JP, Xia F, Bi W, Kang SL, Patel A, Krantz ID, Raible SE, Smith W, Cristian I, Torti E, Juusola J, Millan F, Wentzensen IM, Person RE, Küry S, Bézieau S, Uguen K, Férec C, Munnich A, van Haelst M, Lichtenbelt KD, van Gassen K, Hagelstrom T, Chawla A, Perry DL, Taft RJ, Jones M,
Masser-Frye D, Dyment D, Venkateswaran S, Li C, Escobar LF, Horn D, Spillmann RC, Peña L, Wierzba J, Strom TM, Parenti I, Kaiser FJ, Ehmke N, Schaaf CP. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet Med. 2019 Jan 25. doi:10.1038/s41436-019-0433-1. [Epub ahead of print]


Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling.

We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency.

The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination.

The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Monday, July 29, 2019

Maternal migraine and infant colic

Mothers, but not fathers, with migraine are significantly more likely to have an infant with colic, new research suggests.

In a large cross-sectional study, infants 4 to 8 weeks old were 70% more likely to have colic when born to mothers with migraine compared with babies born to unaffected women.

"There was a clear association no matter how we asked about migraine," lead author Amy Gelfand, MD, University of California, San Francisco, told attendees here at the American Headache Society (AHS) Annual Meeting 2019.

"Infant colic being associated with migraine really opens up a door for us to think what migraine looks like in the developing brain," she said. "People will ask me if these babies are really having a headache. Clearly, they are experiencing distress." 

Gelfand noted that the babies with colic could be inheriting an increased sensitivity to stimuli. 

"They may be experiencing the fundamental migraine [experience] and expressing it in the only way they can," she said.

Previous case-control studies examining an association between migraine and infant colic were limited by "some recall bias," Gelfand said.

Conversations about symptoms sounded very similar when she was a child neurology resident talking to parents of children with colic and when she did a headache rotation and talked to patients with migraine.

As reported by Medscape Medical News, Gelfand conducted a smaller cross-sectional survey study during her residency to find out more. Among the 154 mother–baby pairs, 22 infants had colic and 28 mothers reported migraines.

"We found mothers with migraine were more than 2.5 times as likely to have a baby with colic," she said.

The current study builds on her previous findings. 

The investigators assessed responses to a web-based survey from 827 biologic mothers and 592 biologic fathers of infants 4 to 8 weeks old.

They used the same question to identify infants with colic as the first study: "Has your baby cried for at least 3 hours at least three times in the past week?" A total of 26% of babies met this criterion for colic.

Researchers also asked about migraine in a number of ways, including self-report. Participants were asked if a physician had ever diagnosed them with migraine and through screening using the modified International Classification of Headache Disorders, 3rd edition, criteria.

Of the participating mothers, 33.5% were classified as having migraine or probable migraine.

Results showed that maternal migraine was linked with an increased likelihood of infant colic (odds ratio [OR], 1.7; 95% CI, 1.3 - 2.4). The findings held when the researchers controlled for anxiety and depression as possible confounders.

Gelfand noted a "dose effect" as well. Mothers who reported migraines on 15 days or more per month were even more likely to have an infant with colic (OR, 2.5; 95% CI, 1.2 - 5.3).

In contrast, paternal migraines were not associated with higher odds for infant colic (OR, 1.0; 95% CI, 0.7 - 1.5). A total of 19% of fathers reported migraines.

"Paternal migraine was not associated with infant colic no matter how we looked at it," Gelfand said. "We had enough numbers that if it was there we would have expected to see it."

Experts have proposed many theories of what causes infant colic, including a gastrointestinal etiology, Gelfand said.

However, "there is pretty limited evidence of thinking of colic as a gastrointestinal problem," she noted.

She added that X-rays in a small number of studies have shown no extra-abdominal gas; that simethicone does not seem to improve colic; and whether the baby is fed by breast, bottle, or both does not seem to be related.

"For me, the thing that is most indicative that we are not dealing with a feeding phenomenon is that it peaks in the evening, [whereas] feeding at this age is around the clock," Gelfand said.

"I would like to introduce the concept of infant crying as a neurodevelopment process," she said.

In general, colicky crying peaks at 5 or 6 weeks post gestational age, so it could be something that involves neuronal maturation, Gelfand added.

"Infant crying may be a brain-driven process rather than a belly-driven process," she said.

The mechanism underlying the link between maternal migraine and infant colic remains unknown.

Mitochondrial genetics passed down from a mother is one theory, Gelfand said. It might also be a different epigenetic phenomenon or a social effect, "such as a difference in how mothers perceive crying versus how fathers perceive it."

"Are these babies inheriting genes that make them more sensitive to stimuli? We're now getting into post hoc/exploratory data territory," she said. "For us as a field, this is just a tremendous opportunity moving forward."

In terms of clinical implications, "If you are seeing a woman with migraine who is pregnant or considering pregnancy, I think it is worthwhile to counsel them about increased likelihood of having a baby with colic," Gelfand said. "Assure them it's a time-limited phenomenon."

In addition, "maybe if you have a colic baby you do not need to buy special formula, maybe you need to decrease the stimuli they are encountering," she noted.

The researchers are now conducting a pilot study in 20 babies to measure and report minutes of daily crying.

Commenting for Medscape Medical News, chair of the AHS meeting's Scientific Committee Andrew C. Charles, MD, a neurologist at the University of California, Los Angeles Medical Center, noted that the research is "part of this changing concept of migraine" as a disorder that can present in a variety of different ways at different times of life.

"It's not utterly definitive, but it's strong enough to be provocative," said Charles, who was not involved with the study.

"The other point she makes is that colic has often been assumed to be a gastrointestinal (GI) issue. But there is no evidence for that; it's defined as 'inconsolable crying'," Charles noted.

"So the whole idea that it's a GI problem is just dogma that's been around a long time without any particular evidence," he concluded.

The research earned Gelfand the Harold G. Wolff Award, recognizing the best paper on headache, head, or face pain, or the nature of pain itself. Gelfand and Charles have reported no relevant financial relationships.

ECHS1 mutations

Inspired by a colleague's patient

Ferdinandusse S, Friederich MW, Burlina A, Ruiter JP, Coughlin CR 2nd, Dishop MK, Gallagher RC, Bedoyan JK, Vaz FM, Waterham HR, Gowan K, Chatfield K, Bloom K, Bennett MJ, Elpeleg O, Van Hove JL, Wanders RJ. Clinical and biochemical characterization of four patients with mutations in ECHS1. Orphanet J Rare Dis.2015 Jun 18;10:79.


Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics.

Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients.

All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased.

Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.

Ganetzky R, Stojinski C. Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency. 2019 Jun 20. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. 


Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described: The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion. Across all three groups, T2 hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.

The diagnosis of ECHS1D is established in a proband by the identification of biallelic pathogenic variants in ECHS1 on molecular genetic testing or low short-chain enoyl-CoA hydratase (SCEH) activity using cultured skin fibroblasts.

Treatment of manifestations: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia (which may be related to severe acidosis or low ATP from impaired aerobic oxidation) may be addressed by treatment of the metabolic acidosis and/or consideration of hemodialysis. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Standard treatment for seizures, cardiomyopathy, pulmonary hypertension, optic atrophy, sensorineural hearing loss, and developmental delay. Surveillance: At least annual echocardiogram, dilated eye examination, and audiologic evaluation. Routine monitoring for neurologic symptoms and developmental issues. Assessment of acid/base status and blood lactate level with all illnesses or metabolic stressors. Agents/circumstances to avoid: Mitochondrial toxins (i.e., valproic acid, prolonged propofol infusions); ketogenic diet.

ECHS1 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% change of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the ECHS1 pathogenic variants in the family are known.

Aretini P, Mazzanti CM, La Ferla M, Franceschi S, Lessi F, De Gregorio V, Nesti C, Valetto A, Bertini V, Toschi B, Battini R, Caligo MA. Next generation sequencing technologies for a successful diagnosis in a cold case of Leigh syndrome. BMC Neurol. 2018 Jul 20;18(1):99.


Leigh Syndrome (LS, OMIM 256000) is an early-onset, progressive neurodegenerative disorder characterized by broad clinical and genetic heterogeneity; it is the most frequent disorder of mitochondrial energy production in children. LS inheritance is complex because patients may present mutations in mitochondrial DNA (mtDNA) or in nuclear genes, which predominantly encode proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis. However, during the last 15 years, the discovery of several genetic mutations and improved knowledge of the natural history of LS has significantly increased our understanding of this mitochondrial disorder.

Here we describe a 19-year-old male with clinical and neuroimaging LS diagnosed at 3 years of age. Genetic analyses of the whole mtDNA for maternally inherited LS (MILS) and neuropathy ataxia retinitis pigmentosa (NARP) syndrome failed to reveal any pathogenic mutations.

Recently, a missense mutation in ECHS1 and a ~ 35 kb deletion in 10q26.3 involving the region including the gene were identified by WES (whole exome sequencing), uncovering the genetic diagnosis clinically hypothesized for 15 years. We also report the long-term follow-up of this patient, showing a comparison with classical LS or other Leigh-like pictures.

ECHS1 gene; Exome analysis; Leigh disease

Saturday, July 27, 2019

Adrenal medullary hypoplasia

Doug Lindsay was 21 and starting his senior year at Rockhurst University, a Jesuit college in Kansas City, Missouri, when his world imploded.

After his first day of classes, the biology major collapsed at home on the dining room table, the room spinning around him.

It was 1999. The symptoms soon became intense and untreatable. His heart would race, he felt weak and he frequently got dizzy. Lindsay could walk only about 50 feet at a time and couldn't stand for more than a few minutes.

"Even lying on the floor didn't feel like it was low enough," he said.

The former high school track athlete had dreamed of becoming a biochemistry professor or maybe a writer for "The Simpsons."

Instead, he would spend the next 11 years mostly confined to a hospital bed in his living room in St. Louis, hamstrung by a mysterious ailment.

Doctors were baffled. Treatments didn't help. And Lindsay eventually realized that if he wanted his life back, he would have to do it himself…

Whatever was wrong with him ran in the family.

By the time Lindsay was 18 months old, his mother was so weak she could no longer pick him up.
By the time he was 4 she could no longer walk. She did manage to pick him up one more time that year, when he was choking on a jawbreaker. She saved his life.

Otherwise, she was too frail. She lived for decades, mostly bedridden with the same condition that stole her son's twenties. After years of tests, she determined her condition was related to her thyroid, but she was too sick to travel to the Mayo Clinic to get more specialized care, Lindsay said.

Lindsay's aunt also developed the same ailment, growing so feeble she couldn't tie her own shoes…
From the fall of 1999 onward, Lindsay was bedridden about 22 hours a day.

"If I was up, it was because I was eating or going to the bathroom," he said.

Lindsay immersed himself in medical research, determined to find a way out. He saw specialists from endocrinology, neurology, internal medicine and other specialties. When one doctor was out of ideas, he referred Lindsay to a psychiatrist.

That's when Lindsay he realized he'd have to figure his predicament out on his own…

He zeroed in on his adrenal glands, which sit atop the kidneys on either side of the lower abdomen…
Lindsay suspected his body was producing too much adrenaline. He knew of a drug called Levophed, which is approved by the US Food and Drug Administration to raise blood pressure in some critically ill patients. Levophed is basically an injection of noradrenaline, which counters the symptoms created by excess adrenaline.

Dr. H. Cecil Coghlan, a medical professor at the University of Alabama-Birmingham, approached Lindsay after his presentation. Coghlan said he thought Lindsay was on to something.

At last, Lindsay had a medical ally.

It hadn't been done before, but Lindsay convinced Coghlan to repurpose the drug so he could live on a 24/7 noradrenaline drip for the next six years.

Lindsay spent "every second of every day" hooked up to an IV. It stabilized his condition and allowed him to be active for short periods of time around the house.

"I was no longer at risk of losing everything," Lindsay said…

Still, other than doctors' visits, a high school reunion and a few weddings, Lindsay's autonomic dysfunction kept him mostly confined to the house he grew up in well beyond his twenties.

Why was he so sick, he wondered? Something was dumping way too much adrenaline into his blood.
Coghlan told him he might have an adrenal tumor. But three scans of his adrenal glands all came back negative…

A fourth scan in 2006 showed his adrenals "glowing brightly," Lindsay said, an abnormality consistent with his new theory.

Coghlan called Lindsay and said, "We found it!" The diagnosis: bilateral adrenal medullary hyperplasia…

And he fixed on what seemed like a simple solution: If he could cut out the medullas of his adrenal glands -- sort of like slicing into a hard-boiled egg and removing the yolk -- his health would improve…

Eventually he recruited a surgeon from the University of Alabama-Birmingham. In September 2010 Lindsday went to the university hospital, where the doctor successfully extracted one of his adrenal medullas.

Three weeks after the procedure, Lindsay could sit upright for three hours. By Christmas Eve, he had the strength to walk a mile to church.

As he stood in the back of the church during midnight Mass, it finally felt like hope was winning.
But progress was slow. In 2012, he underwent a second surgery at Washington University in St. Louis to remove the medulla from his remaining adrenal gland.

A year later, he was well enough to fly with friends to the Bahamas. It was the first time in his life the Midwesterner had seen the ocean.

By early 2014, he was coming off some of his meds…

Today he still lives in his childhood home in St. Louis. He needs to take nine medications per day, and his health is far from perfect, but he has his life back.

He's not exactly the biology professor he dreamed of being at 21, but he's not far off the mark. He's leveraging his experience into a new career as a medical consultant.

Courtesy of a colleague

Friday, July 26, 2019

PAM is a very bad thing. Primary amoebic meningoencephalitis.

A swimmer has died after contracting brain-eating amoeba at a water park in North Carolina, according to reports.

The swimmer was exposed to Naegleria fowleri, an amoeba commonly found in warm freshwater, at Fantasy Lake Water Park in Cumberland County on July 12, Fox 46 Charlotte reported.
The news outlet added that were just 145 known cases of infected Americans from 1962 through 2018.

North Carolina had five cases during that time period. 

"Our sympathies are with the family and loved ones," Dr. Zack Moore, the state’s epidemiologist, told Fox 46. "People should be aware that this organism is present in warm freshwater lakes, rivers and hot springs across North Carolina, so be mindful as you swim or enjoy water sports."

PAM is a very bad thing. Not PAM the cooking spray or Pam from The Office but PAM as in primary amoebic meningoencephalitis.

This condition can occur when Naegleria fowleri, a type of amoeba, goes up your nose, makes it to your brain, and starts eating your brain. Getting your brain eaten by an amoeba is rare but bad, since your brain is pretty important and helps you text and do other stuff like live. In fact, nearly everyone who gets such PAM ends up dying.

The most recent reported case and death just occurred in North Carolina when a person became infected with the brain-eating amoeba after swimming in the Fantasy Lake Water Park, as reported by Stephanie Towers reported for WYFF News 4.  Naegleria fowleri tend to live in warmer fresh water, such as lakes, rivers, hot springs, poorly chlorinated swimming pools, water in water heaters, or water from industrial plants.

You can't get infected by Naegleria fowleri from simply drinking contaminated water. In this case, the best way to your brain is not through a book or a TED Talk but up your nose. The amoeba has to go up your nose to get to your brain. And since N. fowleri don't ride e-scooters, water containing the amoeba has to be forced up your nose. This can occur when you dive into or dunk your head into contaminated water. It can also happen when you irrigate your nose with non-sterile water for religious or other reasons like using a neti pot. As I have written before for Forbes, tap water and french fries are two things that shouldn't go up your nose. N. fowleri can also be found in soil. However, unless you are an aardvark or literally a brown nose, you probably don't tend to shove soil up your nose.  

After getting infected, you may start to notice symptoms in one to nine days (an average of five days) such as a fever, a headache, nausea, or vomiting. This can seem like the flu, but soon other symptoms related to inflammation of the brain and the membranes around the brain occur, such as getting stiff neck, becoming confused, having hallucinations, losing your sense of balance, suffering seizures, and lapsing into a coma. The disease progresses pretty quickly and many times death results within 5 days. All of this, of course, sounds terrible unless you are a brain-eating amoeba.

Fortunately, N. fowleri infections of the brain are very rare with only 145 documented cases in the U.S. from 1962 to 2018, according to the Centers for Disease Control and Prevention (CDC). Unfortunately, though, only 4 of these cases managed to survive. As seen in this ABC News segment, Kali Hardig, 12-years-old at the time, became the third person in the U.S. to survive in 2013:


In early July of 2015, a group of friends and family gathered at a home in Orlando, Florida, to celebrate 11-year-old Jordan Cole Smelski, a fun-loving thrill seeker who excelled at sports, academics and making people laugh.

“We decided to have a party, I think we had 75 people over to the house,” Jordan’s father, Steve Smelski, told AccuWeather. “We cooked Jordan’s favorite, which was a special type of hamburger that he liked, and we had burgers for everybody.” It’s the kind of gathering you’d typically expect for special occasions, like birthdays.

Except this occasion was quite different.

Steve and his wife, Shelly, spent time with family and friends until around 6 p.m. that evening. “Then, it kind of became overwhelming, and we snuck off to our room,” Smelski said. “It’s a very emotional day.”

It was not Jordan’s birthday that those who knew him were recognizing. He would have turned 13 later that year on Nov. 9, 2015.

Instead, loved ones had gathered that July in remembrance of a young life cut short just a year prior. On July 2, 2014, Jordan lost his battle with primary amebic meningoencephalitis (PAM), an illness he contracted during a swim in a freshwater pool in Costa Rica, where he was infected with Naegleria fowleri, commonly known as the brain-eating amoeba.

Now, five years after Jordan’s tragic death, the unexpected loss remains difficult to cope with for his parents, who were devastated by the loss of their only child. The inseparable trio had been known as the “three amigos” during Jordan’s lifetime. 

“We went from having a child who was 11-and-a-half, graduating elementary school and getting ready to go to middle school, and now, we’re empty nesters,” Smelski said. “We’ve missed out on the high school years, college years, graduation, seeing him have a girlfriend or learning to drive.”

How the nightmare began

The life-altering moment for the Smelski family started out in the most unexpected of ways — following an enjoyable, leisurely six-hour swim in their Costa Rican resort’s pool in 2014. The family was wrapping up their nine-day vacation in late June. They normally planned fun getaways at least once each summer, and had previously visited Costa Rica and the same resort in 2011. Before the swim that rocked their worlds forever, the 2014 adventure started out as a “good vacation,” Smelski recalled. “We went horseback riding a couple of times. We did ziplining. Jordan loved to zipline. The scarier, longer and faster, the better for him.”

Near the end of the trip, Smelski and his son went for a dip in a pool with a water slide. It was filled with non-chlorinated hot spring water, and repeatedly going down the water slide had forced water up their noses each time they splashed into the pool.

Unbeknownst to them at the time, lurking within the freshwater was Naegleria fowleri. While Jordan’s dad had experienced no ill health effects following the swim, Jordan was not as fortunate.

His symptoms began with a headache the following day. His parents treated him with Motrin. Over next few days as they wrapped up their trip and traveled back home to Orlando, the throbbing headache persisted.

“We got up Saturday morning and he still had a headache, but he was playing video games all morning,” Smelski said. “We had him sit down, and by afternoon, he was lying down and wasn’t playing video games, so he definitely wasn’t feeling well.”

By 11:30 that evening, Jordan went to bed and began vomiting. It lasted through the night. His parents’ worries mounted as the fourth day approached and Jordan's headache remained constant. They wondered if he’d caught something while they were out of the country. They took him to the hospital on Sunday, June 29, 2014.

Doctors gave Jordan medication to treat the vomiting and headache, and decided that a lumbar puncture was needed to test his cerebral spinal fluid. Jordan had added a stiff neck to his growing list of ailments, and doctors assumed he might have some type of meningitis. Following a CT scan, it was revealed that Jordan was suffering from viral meningitis -- or so it appeared.

“The problem with PAM is it masks itself as something else,” Smelski said. Having known virtually nothing about the disease and Naegleria fowleri before his son’s death, he’s become an expert on the topic in the years since. “It can look like viral meningitis early in the infection. A day or two later, it can look like bacterial meningitis or encephalitis. There’s no initial test for it; you have to know what you’re looking for, and it’s very hard to find.”

Eleven-year-old Jordan Smelski ziplines through trees on a family vacation in Costa Rica in June 2014 — just days before falling ill with primary amebic meningoencephalitis (PAM). (Photo/Steve Smelski) 

2 hours too late

Jordan was then admitted to a children's hospital, and while Sunday night was rough for him, his condition seemed to improve a little as Monday began. However, around 8:45 p.m., Jordan’s headache began to explode once again. “[It was] like a nine on a scale of one to 10,” his father recalled.

Nurses gave the ailing child morphine, hoping to lessen his pain. Not long after the morphine entered his system, Jordan’s pupils began dilating and he started hallucinating. “He wasn’t making much sense,” Smelski said. “That went on for about four-and-a-half hours.”

It got to the point where Jordan’s parents would lie down on top of him to prevent his uncontrollable movements from popping out his IVs. “He had this look in his eye like he didn’t know where he was,” Smelski remembered. Then, Jordan had a seizure.

He was eventually moved to the intensive care unit, and after doctors noticed his sodium levels were low, they put Jordan on saline. He seemed better, more stable, Smelski told AccuWeather.

“Doctors came the next morning, which was Tuesday, a week after we swam,” he said. “They told us, ‘It’s going to be two or three weeks, but he’s going to be fine, you’ll be able to take him home.”

But Jordan would never return home. He’d never play soccer or video games, or ride roller coasters ever again.

By Tuesday night, the swelling inside of Jordan’s skull had become so bad, doctors worried that it would push down on his brain stem, which would kill him.

With his parents’ permission, the neurosurgeon drilled into the top of Jordan’s head in an effort to save his life. “That’s the cerebral spinal fluid sample they got out that showed the amoeba,” Smelski said. His parents initially thought finding the source of the problem was a good thing — until they learned that the fatality rate after infection with the amoeba is over 97 percent. Of 145 known infected individuals in the United States between 1962 and 2018, only four have survived, according to the Centers for Disease Control and Prevention (CDC). The amoeba normally kills its host with 12-14 days after symptoms surface.

The drug that could have saved Jordan, miltefosine, was on its way from the CDC in Atlanta. The plane carrying the drug landed in Orlando two hours after Jordan died. 

The ‘rare’ amoeba

Jordan had contracted the Naegleria fowleri amoeba in the only known way that humans can be infected: through contaminated water entering the nose. The amoeba travels up the nasal passage and to the brain, where it destroys tissue. “Exposure usually happens during recreational activities in freshwater, where people have their head underwater and water may be forced up the nose, mainly when they’re jumping in or they’re doing flips in the water,” Trisha Robinson, supervisor of the waterborne diseases unit of the Minnesota Department of Health, told AccuWeather.

Minnesota saw two fatal cases of amoeba infection in 2010 and 2012, both associated with exposure at the same lake. “The water temperature [in those cases] was 73 degrees Fahrenheit,” Smelski said. “If it can happen in Minnesota, it can happen in any state in the U.S., so when people say, ‘it’s just the warmest months,’ that’s not the case.”

Naegleria fowleri can be found in any body of freshwater. Drinking contaminated water, however, will not sicken a person.

The CDC states that the heat-loving organism grows best at higher temperatures up to and sometimes exceeding 115 F. “It can survive all the way down to 40 degrees, which is a lot lower than anybody thought it could survive,” Smelski said.

Florida and Texas have seen the most cases, although the amoeba can be found in freshwater anywhere in the U.S. It can’t survive in sea water.

“The fact that Jordan swam once [and became infected] lets you know that you play Russian Roulette every time you allow your kids in that water, because it’s in every fresh body of water,” Smelski said.

Raising life-saving awareness

Right now, PAM, the illness caused by Naegleria fowleri, is reported by health departments in only three states — Florida, Louisiana and Texas — but is tracked nationally by the CDC on an informal basis. “With 47 states not having to report it, nobody looks for it,” Smelski said.

Through the Jordan Smelski Foundation that was started months after Jordan’s passing, his parents and their board of directors made up of family friends and those who knew Jordan began working to raise global awareness of PAM, especially for medical professionals.

“We now know that by using miltefosine and other drugs, lowering body temperature and inducing coma, the patient can actually come out of it in pretty good shape, whereas before, it was almost always fatal,” Smelski said.

Each year, the foundation hosts the PAM Summit, which invites medical experts from across the country to learn and speak about the illness and better ways to catch it early enough to save lives. The summit is now in its fourth year, and the next event takes place in September 2019.

“We worked with doctors at the first PAM Summit to come up with a care pathway change for hospitals, so that if a patient comes in and is diagnosed with meningitis, it throws an alert into the system that says, ‘You need to check and see if the patient had freshwater exposure up the nose in the last 14 days,’” Smelski said. “It’s an alert [for ruling out PAM and Naegleria fowleri] before you move on and call this a meningitis case. We’ve been trying to share that with as many hospital systems as we can.”

The foundation has also worked to make miltefosine available in more medical facilities. “It needs to be local. It can’t be shipped on a plane because every minute counts, and when the drug is being flown to the patient, you lose many hours.”

In the hours, days and years that have passed since they lost Jordan, the one day that Steve Smelski would give anything to go back and change is June 24, 2014 — the fateful day that he and Jordan went swimming.

“We don’t want to see anyone else go through that, so that’s why we’re continuing to do what we’re doing,” he said.


STXBP1 encephalopathy

Lanoue V, Chai YJ, Brouillet JZ, Weckhuysen S, Palmer EE, Collins BM, Meunier FA. STXBP1 encephalopathy: Connecting neurodevelopmental disorders with α-synucleinopathies? Neurology. 2019 Jul 16;93(3):114-123.


De novo pathogenic variants in STXBP1 encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.

Thursday, July 25, 2019

Bone marrow transplant gone awry

The fiancée of a beloved New Jersey high school principal who died earlier this year while attempting to donate bone marrow to a child has filed a wrongful death lawsuit alleging that doctors treating him were negligent.

Derrick Nelson was described as a man of dignity and courage by his fiancée Sheronda Braker, who is the mother of his 5-year-old daughter.

Braker filed a lawsuit in Union County Superior Court on Monday for malpractice involved in the treatment of Nelson.

The defendants are Jerry Baratta, Hackensack University Medical Center, Hackensack Anesthesiology Associates of New Jersey Healthcare Specialists, The John Theurer Cancer Center and unnamed doctors and nurses overseeing Nelson's care.

Braker is demanding a jury trial and unspecified compensation.

"I'm seeking justice for the untimely death of Derrick," Braker told CNN.

Nelson underwent the procedure to donate bone marrow at Hackensack University Medical Center in New Jersey on February 18 to help an anonymous 14-year-old boy suffering from cancer in France.
For months, Nelson had been in touch with Be the Match -- a foundation that manages a global marrow registry to help those who suffer from blood cancers, said Braker. They informed him that he was a match for the boy.

Nelson, who was the principal of Westfield High School, told the school newspaper before the surgery, "If it's just a little bit of pain for a little bit of time that can give someone years of joy, it's all worth it."

The medical team kept Nelson under anesthesia despite his low oxygen level, according to Braker's complaint.

The complaint alleges the medical team then failed to supply him with additional oxygen, at which point Nelson's heart rate slowed down. This was a late sign of hypoxemia, meaning he had low levels of oxygen in his blood, the complaint says.

Finally realizing Nelson's heart rate had slowed, the medical team attempted to provide ventilation through a mask airway -- but once again failed to provide sufficient care, according to the complaint.
This led Nelson to suffer permanent brain injury, the complaint says. He fell into a comatose state and remained on life support until the 44-year-old man died in April, said Braker's attorney David Mazie.
"This is not a situation where we want people to be worried about and not to proceed with donating bone marrow," Mazie told CNN. "The case is about an anesthesiologist who didn't do what he was supposed to do. This doctor didn't do his job."

Nelson was overweight and had sleep apnea, two factors that put him at a higher risk for undergoing anesthesia, according to the complaint.

One of the defendants, anesthesiologist Jerry Baratta, did not return telephone call and e-mail requests for comment. Baratta is board certified and has been in practice for nearly 30 years, according to the Osteopathic Board of New Jersey.

Hackensack Anesthesiology Associates did not respond to a request for comment.

Mary Jo Layton, a spokesperson for Hackensack Meridian Health, which owns Hackensack University Medical Center, said, "We were saddened by the tragic death of Dr. Derrick Nelson and have shared our deepest sympathies with his family, his students, the community, his friends and colleagues he touched."

"He leaves a remarkable legacy as an educator and veteran. It is important to note that the safety of our patients remains our primary focus."

A military veteran, Nelson's "kindness, compassion, integrity and endlessly positive attitude" touched those he knew, wrote superintendent of Westfield Public Schools, Margaret Dolan, in a letter to parents following Nelson's death.

"We want to prevent this from happening to anyone else," Braker told CNN. "Our family has been forever changed."

Now they tell me

Shi Z, El-Obeid T, Riley M, Li M, Page A, Liu J. High Chili Intake and Cognitive Function among 4582 Adults: An Open Cohort Study over 15 Years. Nutrients. 2019 May 27;11(5).


We aimed to examine the association between chili intake and cognitive function in Chinese adults. This is a longitudinal study of 4852 adults (age 63.4 ± 7.7) attending the China Health and Nutrition Survey during 1991 and 2006. Cognitive function was assessed in 1997, 2000, 2004 and 2006. In total, 3302 completed cognitive screening tests in at least two surveys. Chili intake was assessed by a 3-day food record during home visits in each survey between 1991 and 2006. Multivariable mixed linear regression and logistic regression were used. Chili intake was inversely related to cognitive function. In fully adjusted models, including sociodemographic and lifestyle factors, compared with non-consumers, those whose cumulative average chili intake above 50 g/day had the regression coefficients (and 95% CI) for global cognitive function of -1.13 (-1.71-0.54). Compared with non-consumers, those with chili consumption above 50 g/day had the odds ratio (and 95% CI) of 2.12(1.63-2.77), 1.56(1.23-1.97) for self-reported poor memory and self-reported memory decline, respectively. The positive association between chili intake and cognitive decline was stronger among those with low BMI than those with high BMI. The longitudinal data indicate that higher chili intake is positively associated with cognitive decline in Chinese adults in both genders.

Tuesday, July 23, 2019

A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex

Overwater IE, Rietman AB, Mous SE, Bindels-de Heus K, Rizopoulos D, Ten Hoopen LW, van der Vaart T, Jansen FE, Elgersma Y, Moll HA, de Wit MY; ENCORE Expertise Centre for Neurodevelopmental Disorders. A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology. 2019 Jul 9;93(2):e200-e209.


To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC).

In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems.

Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events.

Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group.


This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.

Risks of malformations associated with prenatal exposure to 10 antiepileptic drugs

Blotière PO, Raguideau F, Weill A, Elefant E, Perthus I, Goulet V, Rouget F, Zureik M, Coste J, Dray-Spira R. Risks of 23 specific malformations associated with prenatal exposure to 10 antiepileptic drugs. Neurology. 2019 Jul 9;93(2):e167-e180.


To assess the association between exposure to monotherapy with 10 different antiepileptic drugs (AEDs) during the first 2 months of pregnancy and the risk of 23 major congenital malformations (MCMs).

This nationwide cohort study, based on the French health care databases, included all pregnancies ≥20 weeks and ending between January 2011 and March 2015. Women were considered to be exposed when an AED had been dispensed between 1 month before and 2 months after the beginning of pregnancy. The reference group included pregnant women with no reimbursement for AEDs. MCMs were detected up to 12 months after birth (24 months for microcephaly, hypospadias, and epispadias). Odds ratios (ORs) were adjusted for potential confounders for MCMs with at least 5 cases. Otherwise, we calculated crude ORs with exact confidence intervals (CIs).

The cohort included 1,886,825 pregnancies, 2,997 of which were exposed to lamotrigine, 1,671 to pregabalin, 980 to clonazepam, 913 to valproic acid, 579 to levetiracetam, 517 to topiramate, 512 to carbamazepine, 365 to gabapentin, 139 to oxcarbazepine, and 80 to phenobarbital. Exposure to valproic acid was associated with 8 specific types of MCMs (e.g., spina bifida, OR 19.4, 95% CI 8.6-43.5), and exposure to topiramate was associated with an increased risk of cleft lip (6.8, 95% CI 1.4-20.0). We identified 3 other signals. We found no significant association for lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, and gabapentin.

These results confirm the teratogenicity of valproic acid and topiramate. Because of the small numbers of cases and possible confounding, the other 3 signals should be interpreted with appropriate caution.