Wednesday, November 25, 2020

BPAN

Wearing a white T-shirt with a massive star in sparkling shades of pink, yellow and seafoam green on the front, Morgan Kozole sits in front of a fold-up chalkboard in the living room of her family's Detroit-area home and starts to draw.

Using pink and yellow chalk, she sketches Mickey and Minnie Mouse. The Disney characters are dominant fixtures in the 5-year-old's life and therefore become a soundtrack for the Kozole family: Morgan constantly saying "Mickey," with her long, blond ponytail bouncing to whatever song happens to be playing on the Mickey Mouse Club.

"These are the two Mickeys," Morgan says, pointing to the chalkboard. Her mother, Detroit Lions senior vice president of business development Kelly Kozole, explains that this is her way of communicating that she would like a visitor to draw Mickey too. If it's close, Morgan accepts it. Another Mickey to fawn over.

For Morgan's birthday earlier this year, the family went to Disney World. On this trip, the Kozoles saw what they had longed for: the potential of progress.

"She knew where we were. She knew Mickey Mouse," Kelly said. "Before, she wouldn't go to the characters, and now she's jumping up and down, hugging. She really, along those lines, is also really into birthdays.

"The 'Happy Birthday' song. Before that, she was just kind of looking. Sometimes it was too much for her with everyone singing -- sometimes loud noises are too much. This year, we had to sing 'Happy Birthday' to her three times."

Birthdays, for children, are happy occasions -- reasons for grand celebrations of progress toward adulthood. For the rest of Morgan's family it is more complicated.

Morgan has a rare neurological disease called beta-propeller protein-associated neurodegeneration, known as BPAN. It's a disorder, more prevalent in girls than boys, that causes delayed development and seizures, communication issues and, sometimes, motor dysfunction. It's unclear exactly how many people are living with BPAN worldwide due to its rarity, although Dr. Sami Barmada, a scientist at the University of Michigan studying BPAN, estimates roughly 500 to 600 people.

It's rare enough that Dr. Henry Paulson, the director of the Michigan Alzheimer's Disease Center, said there are experts in neurodegeneration who are unfamiliar with BPAN. While Kelly is trying to advocate for her daughter and others with BPAN through fundraising for research, science moves only so fast.

The Kozoles understand that. So birthdays for the family aren't always happy. They are a reminder of what could come.

"That ticking time clock," Kelly said. "Every birthday isn't exciting for me for her. Because it's one year closer to when this bomb is going to go off." 

BPAN's rarity makes the reality heartbreakingly simple: There are very few effective treatments, little research and no cure. As Morgan learns how to organize her Peppa Pig characters and learns new words on her iPad -- her future looms.

At some unpredictable point in Morgan's teen and adult years -- the average is around age 25, according to Barmada -- development will just stop. Progress will decline and, in some cases, disappear. Those afflicted with BPAN begin suffering from progressive dystonia parkinsonism -- making it difficult to walk, talk or stand.

"Any day," Kelly said, "it could be like, 'Oh, your daughter's gone.'"

When Morgan was born on Jan. 12, 2015, she was, largely, a healthy baby. She was a little jaundiced but nothing worrisome.

When she would go to the doctor's office for shots, Morgan didn't cry. It was a little abnormal, but when you're a parent of a young child, no crying is viewed as a minor miracle. Kelly and her husband, Kevin, took this as a sign of a tough kid. Nurses even said how great it was.

Looking back, it was a warning sign that something was wrong. BPAN causes a high pain tolerance. Before long, more concerns popped up. Morgan wasn't crawling at nine months, wasn't walking at a year. Expected milestones passed without Morgan reaching them. Kevin and Kelly put her in therapy in late 2016 to work up to these childhood progressive traits and began researching potential causes. They wouldn't find an answer for more than two years.

"She was diagnosed with cerebral palsy at first. One doctor diagnosed her with that, and then another, our neurologist, said she doesn't have that," Kelly said. "Then there was speculation but not a full diagnosis she had autism, so we did all the tests for that.

"So through this kind of journey of trying to find out what was wrong, it was exciting that she didn't have something that you were going to this test for, but you still had so many more questions as you were eliminating all these potential diseases that she could have."

Befuddled, they began genetic testing and in November 2018 received a letter about a mutation on Morgan's WDR45 gene. Kelly Googled it, stumbled upon BPAN and freaked out, calling their neurologist. The neurologist told Kelly not to worry -- BPAN was very rare, and Morgan didn't have it.

Doctors diagnosed her with epilepsy because of seizures. Morgan took Keppra, which helped accelerate her vocabulary to about 50 words, typical for a 1-year-old, when she was 3. Then doctors said no, it wasn't epilepsy either. 

Another meeting with another neurologist led to a different diagnosis. Three days after she and Kevin returned to Michigan from Super Bowl LIII in February 2019, they received a call. Doctors figured out what was wrong.

It was BPAN.

"In my mind, it's worse than cancer," Kelly said. "How is this even possible? That this can even be so painful for kids later on in life. You try so hard to gain all these abilities, and then early adolescence or early adulthood, it's just [gone] one day, and I've seen a lot of these stories.

"There's a BPAN Facebook website, and that's where the doctors sent us. There's no cure. There's no therapy. 'Go to this website.' That's what I was told."

For months Kellycried, angry and heartbroken. The Kozoles initially told their families and no one else.

In May 2019, Kelly went to her first Neurodegeneration with Brain Iron Accumulation (NBIA) conference. She met other parents, heard their stories and began the new normal.

She used her skills -- organization, fundraising and business -- to brainstorm ways to help. Hardly anyone had researched BPAN. Without it, there would be no chance for a cure -- not in Morgan's lifetime, which could reach her 40s, and not in the lifetime of those who might come after.

She shared what was happening with her boss, Detroit Lions president Rod Wood, and his wife, Susan, using a website link to explain BPAN. Wood knew something was wrong because of texts and emails saying they had to take Morgan to this specialist or that appointment.

"As that was confirmed and became her reality, she is now able to talk about it, in a way," Wood said. "Because she's full bore on trying to help generate awareness and financial resources to find a cure for it.

"She went from the unknown to the very tragic known to, 'OK, what are we going to do about it?'"

Kelly consulted her aunts, both of whom worked in medicine. Linda Narhi worked in biotechnology for Amgen for more than 30 years; Dr. Diane Narhi was the first female chief of staff at Simi Valley (California) Hospital. From talking with another group of fundraising BPAN parents -- BPAN Warriors -- Kelly found a guide.

"Any day, it could be like, 'Oh, your daughter's gone.'"

If her aunts had not been resources, she might have joined BPAN Warriors. But Kelly admittedly needs to be in control, and this was her daughter. She needed to manage this herself. She created a nonprofit called Don't Forget Morgan.

Kelly's aunts provided guidance, and Wood offered contacts he had in the finance industry and Silicon Valley. Wood and Lions general counsel Jay Colvin sit on the board. Other Lions coworkers -- with Wood's blessing -- built the website, designed the logo and created social media plans and the first pitch video for Don't Forget Morgan's rollout in 2020.

Progress started with a $15,000 grant to help with a mouse model study at Sanford Research in South Dakota, with another, larger, potential grant to come. In recent months, Kelly has focused largely on fundraising, and another parent of a child with BPAN, Christina Mascarenhas Ftikas, has focused on the medical side of the nonprofit.

"This is why I'm here," Kelly said. "I'm supposed to be a vehicle to get all of this awareness and hopefully a cure for BPAN so the child one, two, three, five years from now, there is hope.

"There is no, 'Go to Facebook.' There is something where you can actually give a parent, 'Here's the symptoms to look for.'"

About an hour away in Ann Arbor, Michigan, Kaci Kegler and her husband, Brian, had been in the same Facebook community. Kelly, new to the group and looking for a nearby connection, wrote Kaci a message.

"Hey, my daughter was just diagnosed, could we connect?"

Kaci understood. She did the same thing, reaching out without success in 2016 after her daughter, Elle, was diagnosed. Kaci wanted to be a resource.

They talked for an hour. There wasn't much Kaci could say to soothe her. Kelly pinged a year later with another message: I'm starting a nonprofit. Kaci offered to help.

Despite suffering from BPAN, Morgan is like any other 5-year-old who enjoys playing with her brother, Connor. Michael Rothstein

Days later, on Feb. 28, Kaci and her husband, Brian, an assistant athletic director for development at the University of Michigan, had their yearly fundraiser for BPAN research on Rare Disease Day at Pizza House in Ann Arbor. They met a doctor who had a connection to researchers at Michigan.

"I literally came home and texted [Kelly] and was like, 'Oh my gosh, we may have inroads,'" Kaci said. "We just started texting. I have never met Kelly face-to-face. We still haven't. But we've texted a lot and we've emailed quite a bit.

"It just kind of started."

By summer, they went from nothing to putting pieces in place for a full-fledged research project with a two-year, $140,000 grant for Barmada and Dr. Jason Chua to help start to solve BPAN.

Chua was working on the regulation of autophagy, which is the cleaning out of damaged cells, and studying BPAN became a natural extension of the work he had already been putting in. BPAN alters that in neurons. Barmada said Chua's research provided a "rare win-win situation" to potentially help with BPAN and other diseases too.

"There are a set of questions in BPAN that nobody has the answer to," Barmada said. "And Jason and myself, we just seem to be in the right position, the right place to be able to help out."

The goal is to understand what is happening within BPAN itself and how people end up with it, while also trying to find therapies for existing patients. Within a year, they are hoping to grow stem cells from people with BPAN in their lab, allowing for the creation of their own stem cells missing the WDR45 gene. Then they will try to either replace the gene or "stimulate autophagy through genetic or pharmacologic means," Barmada said. The hope is this can prevent neurodegeneration.

So far, they've hired a research assistant to work with Chua, developed tools to manipulate the gene using the genome-editing tool CRISPR and applied for approval from Michigan and the institutional review board to get skin biopsies to obtain stem cells from BPAN patients.

It's a process, but it's also a start.

After partnering with Michigan and Sanford, Don't Forget Morgan also began working with Dr. Kathrin Meyer, a researcher at the Center for Gene Therapy at Nationwide Children's Hospital at Ohio State.

"Solving this disease is going to require more than Jason and Sami," Paulson said. "It's going to be a first shot across the bow, but it's going to require more than that. I'll say this, being in the field for a long time. Scientists who are coming up the pike say they want to look at Alzheimer's, want to look at epilepsy. They don't say, 'I want to look at a rare disease.'

"The only way to solve a rare disease is to get someone hooked. Sometimes when you hook a really good one, as I think we have with Jason here, you hook them for life and they make a difference."

Morgan is bouncing around the Kozoles' suburban Detroit home on this late August day. They just returned from northern Michigan, and having two kids, especially one with special needs, makes tidiness unrealistic.

COVID-19 changed things. Morgan hadn't been to many of her therapies for months. Online school barely kept her attention. There was concern she would have regression in her learning. Instead, her speech advanced by being around Kelly, Kevin and her older brother, Connor, all day. She has sung more songs recently to help increase her vocabulary. Sometimes, she'll listen 20 times in a row.

"Even more than that," Connor said. They aren't sure how much she's truly learning versus memorization. But it is something.

Morgan Kozole has inspired her mother, Detroit Lions VP Kelly Kozole, to marshal researchers and other advocates to develop a cure for BPAN, and perhaps help future generations of children who live with the disorder. Michael Rothstein

The family gathers inside Morgan's bedroom -- complete with a special Haven Bed with a zipper to keep her safe from wandering around at night, when she could accidentally turn on the stove and hurt herself or others -- sleep disorders are another BPAN issue. She sits on the floor and starts playing with her small, yellow dollhouse and a fake ice-cream maker. Kelly asks for an ice cream. Morgan makes one for herself instead and pretends to eat it.

Later, outside, Morgan kicks a soccer ball and plays a modified game of catch with a squishy football. Football, no surprise, is big. She says "hike" a lot. "She knows that term," Kevin says, laughing.

In these moments, Morgan seems like any other young child. She attends St. Hugo of the Hills Parish School in Bloomfield Hills, Michigan, but has a one-on-one para nanny to help. She interacts with people, often overly affectionate.

Sitting at the kitchen table after playtime outside, she plays with Starfall, a children's learning app, on her iPad. They hope it accelerates her word recognition. Morgan is entranced watching "Farmer in the Dell" and using her hands to eat orange slices and Cheerios. She needs a mirror in front of her to provide her a target for her mouth. She listens to books, another way to try absorbing information.

Morgan can now count to 20 and say three sentences in a row. Kelly and Kevin have tried to give Morgan a normal life in an abnormal situation, but they worry about the future -- what she won't have and won't be able to experience.

But Morgan has changed some of that outlook too.

"Focus on how she is so loving and has so much pure joy. A lot of parents of special needs [kids] say you can learn so much from these kids, and you really can," Kelly said. "She is, every morning, just so happy, and 'Mama!' Hugs and kisses to strangers. She has none of those behaviors you learn as an adult where you're not kind to people or you don't want to talk to someone.

"She is just open arms, will give you a hug and is so loving, and it's like, 'Wow, this is really what life is about.'"

https://www.espn.com/nfl/story/_/id/30371811/detroit-lions-vp-tries-save-daughter-rare-disease

Courtesy of a colleague

See:  https://childnervoussystem.blogspot.com/2018/02/beta-propeller-protein-associated.html

 

Dr. Death revisited 2

Kellie Martin and her husband Don were taking Christmas decorations down from the attic of their suburban Garland, Texas, home in late 2011 when their lives changed forever.

Kellie, 54, missed a step on a ladder and fell, resulting in a herniated disk in her back. After physical therapy and muscle relaxers, their family doctor recommended neurosurgeon Christopher Duntsch. The couple agreed to visit the doctor — a decision that will forever haunt Don and their two daughters.

The case of Duntsch is explored in the new Oxygen docu-series, “License to Kill,” premiering on June 23. The show, hosted by renowned plastic surgeon Dr. Terry Dubrow of “Botched," chronicles the harrowing accounts of patients put into jeopardy by medical professionals’ insidious use of their expertise. It highlights interviews with families, medical professionals and law enforcement.

Duntsch was recently the subject of a true crime podcast earlier this year titled “Dr. Death” by Wondery — the same podcast network behind their hit series “Dirty John.”

“From the initial fall, it wasn’t that super great,” Don told Fox News about his wife’s injury. “It was a lingering pain. It never went away. We did all kinds of treatments to help alleviate the pain, but it just remained persistent. We were planning on going to an out of country trip, so we thought we might get this fixed before we did. And she was in more pain than she led on. I could see it. I didn’t want her to go through that if we could avoid it. That’s when we started exploring surgery options.”

The couple soon found themselves in Dr. Duntsch’s office scheduling surgery for during the elementary school teacher’s March 2012 spring break. Duntsch insisted the 45-minute procedure was routine and simple to do.

 “He sounded very articulate,” reflected Don. “It sounded like he knew what he was doing. We figure it wouldn’t be an issue… He said it was a minor surgery, but that she would be OK after the procedure. A very simple, common procedure — that’s what we were hoping for. A quick recovery."

But on the day of surgery, Don found himself waiting, not knowing what happened to Martin.

“About an hour later, I’m still sitting in the waiting room and I hadn’t heard from anybody,” he explained. “I asked one of the nurses to check and see what was going on. Then 15-20 minutes later, [Duntsch] came out. He tells me the surgery went well and she’s moving around, but was in obvious pain so they gave her more medicine. She may have to go up to the ICU or maybe stay overnight, but she was going to be OK… That’s when I called my daughters to come up to the hospital. That’s when I realized this is not good.”

The wait continued and Don agonized over Martin, wondering what was happening behind closed doors.

 “I’m starting to freak out,” he said. “Something just wasn’t right because no one was telling me, ‘Hey, she’s recovering, you can come to see her.’ Instead, they’re continuing to work on her. This is going on now for two hours. My girls were holding on to hope, but I just knew something was seriously wrong."

Don said the ICU physician, as well as Duntsch and the anesthesiologist, came to see him and the couple’s two daughters to deliver the devastating news — the beloved matriarch was dead.

“They told us they tried everything they could, but they couldn’t save her,” said Don. “That’s when the girls lost it. I lost it. That’s when the nightmare started… We didn’t get a chance to say goodbye to her. We went in there with good faith, believing in the doctors and the medical world so they could help us. Instead, they ended up turning our world upside down. It was pure misery. I was totally lost. My world just ended right then and there.”

People magazine reported the medical examiner confirmed Don’s fears. It turned out Martin had bled to death after Duntsch sliced an artery. According to the outlet, Don also learned that Duntsch had earlier operated on one of the coroner’s office employees and left the man paralyzed. The Dallas County district attorney’s office would later learn that that out of 38 surgeries undertaken by Duntsch in less than two years, 33 had gone wrong. Two patients had died, one was rendered a quadriplegic and many were left with permanent injuries.

“I was angry,” said Don when he learned of Duntsch’s other victims. “I was angry at the medical world. If this doctor had previous bad outcomes, why did he still had the ability to do surgery? It was such a cover-up. As things progressed, I got angrier and angrier with the system. But by the grace of God, other doctors started voicing their opinions about [Duntsch]. But how was I going to survive? How am I going to live day by day now?”

Between 2011 and 2013, Rolling Stone previously reported, Duntsch was employed by four Dallas-area hospitals and nearly all of his patients, those who survived, came out in far worse shape than ever before.

During the trial, Dallas surgeon Randall Kirby, who assisted on one of Duntsch’s surgeries in 2012, told jurors he sent information to the Texas Medical Board, warning them of Duntsch’s botched procedures. D Magazine shared that despite receiving complaints dating back to 2012, the Texas Medical Board reportedly didn’t revoke Duntsch’s privileges until 2013. Texas Observer clarified that the Texas Medical Board is "limited" in its ability to investigate malpractice, which could have possibly resulted in the delay.

According to records, Duntsch was booked into the Dallas County Jail in 2015. He was charged with five counts of aggravated assault causing serious bodily injury and one count of injury to a child, elderly or disabled person.

D Magazine reported that in July 2016, the Dallas County District Attorney’s Office followed through and a grand jury returned five indictments of aggravated assault and one of harming an elderly person. Duntsch pleaded not guilty and alleged in emails that he was at the center of “a vast conspiracy to bilk money from the hospitals where he practiced.”

The indictment accused Duntsch of wide-ranging malpractice, including improper placement of screws and plates along patients’ spines, a sponge left in one patient, and a major vein cut in another. Records also showed that Duntsch operated on the wrong part of a patient’s spine, damaged nerves and left one woman with chronic pain and dependent on a wheelchair.

At the time, Duntsch was struggling financially and had racked up a series of arrests, including stealing Walmart merchandise.

During the trial, prosecutors said Duntsch’s hands and surgical tools amounted to “deadly weapons,” and contended that he “intentionally, knowingly and recklessly” harmed up to 15 of his patients. Prosecutors also claimed that in a 2011 email to a girlfriend, Duntsch said he would “become a cold-blooded killer.”

Dallas surgeon Randall Kirby says his former colleague, Dr. Christopher Duntsch, managed to commit crimes so heinous that patients everywhere are still struck by fear when they hear about the case for the first time.

However, Duntsch’s attorneys argued that he was not a criminal but just a lousy surgeon committing malpractice in chaotic operating rooms in hospitals in Dallas and its northern suburbs. They also said the tone of the email in question was unclear and could have been meant as sarcasm.

The New Yorker reported Duntsch was ultimately stopped after the combined involvement of the Dallas Country district attorney, an attorney, a journalist, and the state medical board with the efforts initiated by Kirby and Dr. Robert Henderson, a veteran surgeon at the Dallas Medical Center.

In 2017, a jury sentenced Duntsch to life in prison for maiming patients who had turned to him for surgery to resolve debilitating injuries. The decision came almost a week after the Dallas County jury convicted Duntsch of first-degree felony injury to an elderly person.

But life for Don and his family still isn’t easy.

“I’m not gonna lie, I think this puts a strain on our relationship a little bit,” said Don about his daughters. “We were such a close-knit family. It was difficult for them. It was difficult for all of us. They were trying to be careful around me, trying not to say anything or do anything that will upset me. My whole lifestyle has changed. Everything is different now. I look at life differently totally differently. Life is just too precious, too short. We can’t take the little things for granted. We’re just trying to make the best of each day.”

Don hopes viewers will be compelled to conduct no-nonsense on any physician or surgeon they’re considering — and to never take any kind of procedure for granted. 

“Get a second opinion no matter what,” he said. “Evaluate everything to make sure you really want to do this surgery. Explore all options. And realize that no surgery is a routine, simple surgery. Everything can be a life or death situation.”

https://www.foxnews.com/entertainment/dr-death-license-to-kill-documentary

Medical mayhem 16

When Patricia Hester was given the news from Dr. Farid Fata that she had cancer in Feb. 2010, she instantly went into survival mode. 

In a concerted effort to get the jump on her diagnosis, Hester – a relatively healthy emergency room technician at the time and now-fitness instructor – against her better judgment of pumping herself with chemotherapy, heeded the advice of Fata and began cancer treatments after looking into Fata’s credentials and performance records. However, there was one big problem, Hester didn’t actually have cancer. 

“It's very surreal. It's an out-of-body experience,” Hester told Fox News of being told she had cancer. “If you're not feeling sick, you don't expect that type of news and so you feel like you're watching this whole interaction go on and you're an observer – you're not actually the person [receiving the news]." 

Hester's story will be featured in the second season of "Dr. Death" from podcast network Wondery, which delves into the mistreatment and misdiagnosing of hundreds of patients who were under the care of Dr. Farid Fata in Michigan. In 2015, a judge sentenced the Detroit-area cancer doctor to 45 years in prison – out of a possible 175 years he was eligible to receive – for collecting millions from insurance companies while poisoning more than 500 patients through needless treatments that wrecked their health.

At the time of his sentencing, Fata offered no excuses before he was handed his punishment. He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering. 

“The sheer volume of the cases was definitely eye-opening,” Wondery podcast producer and director Marshall Lewy said. 

“For one thing, [Fata] was incredibly well respected. He was the most decorated doctor in the area when it came to cancer and oncology and hematology,” Lewy explained when asked how Fata was able to take advantage of so many patients and remain undetected for so long.

On the podcast, George Karadsheh, who was hired in Sept. 2011 as his office manager, described Fata’s office as “grand," complete with expensive art and a piano in its lobby. 

Dr. Farid Fata was sentenced to 45 years in prison in 2015<strong>. </strong>He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering.

Dr. Farid Fata was sentenced to 45 years in prison in 2015<strong>. </strong>He had pleaded guilty in 2014 to 13 counts of health care fraud, one count of conspiracy to pay or receive kickbacks, and two counts of money laundering. (My Fox Detroit) 

He further explained that the bustle of the infusion room “was like a parking lot for chemo chairs,” adding, “it would be like in a barbershop. There was never a moment where that chair wasn't being used.”

Fata shaped a revolving door of some 50 to more than 70 patients who would visit for cancer treatments per day, according to the podcast. In addition, the program reported that Fata only saw them for minutes at a time before he recommended and billed treatments later deemed unnecessary to many of them who had waited hours in the office before seeing Fata. 

“That was only one part of it. And I think the other part was he really built a system where he would have total control,” said Lewy. “So as the years went on, outside referrals he dealt with in-house, he set up his own pharmacy, he set up his own palliative care, the hospice that he would recommend was run by a relative. So it just was this sort of closed-loop where if anybody went to try to get a second opinion, they often ended up with someone who he referred them to.”

So when Fata broke the news to Hester that she had cancer that would likely turn terminal, Hester said she was in a deep state of denial.

“I had recovered from being ill with pneumonia and had chronic asthma. So it was unbelievable,” she lamented. “The first thought was 'No way.' I was in denial, of course. You have so many thoughts flying through your head at the same time and it's like, 'OK, if I'm sick,' before you move on to the next step, first of all, you just have to mull that over.”

Continued Hester: “It's like, 'OK, I'll do everything I can to live my best life, my best quality of life. I'll be as proactive as possible and I'll get on a waiting list for a stem cell.' You know, assuming that this is actually me and this is actually going on, if I'm going to walk out these steps, this is what I'm going to do. I need to beat this. I need to be the healthiest of healthy.”

Hester maintained that despite being in a state of denial and disbelief, “I just knew that I had to do all that I could to avoid a horrific death.”

“People say, 'Oh, I'm going to beat this,' but my thought wasn't to load me up with chemo and if there's a tumor, let's get radiation,' said Hester. “My thoughts were different than where a lot of people would go. Mine were more fight-or-flight. I kind of wanted to bolt, like this wasn't even possible.”

The fallout from Fata’s unnecessary treatments left Hester with severe damage to her teeth and her immune system.

Hester said in the years since she ended Fata's ill-prescribed cancer treatments, she later found out through meetings with another oncologist, who had read her chart, that the damage to her teeth was imminent and likely only happened as a direct result of the previous treatments she had undergone.

“I had two back teeth that I started having problems with, and I was at the dentist, and the dentist was like this tooth looks really weird and there was no problem with it before – and this other tooth is just really strange,” recalled Hester. “And I never have had a bunch of root canals or anything like that so I ended up going to an endodontist and he sent me to an oral surgeon, and then he did surgery and took them out, and he wrote a big paper on it on the fact that this is from overtreatment that was deemed unnecessary.

“I know that sounds small, but that was pretty traumatic,” she added.

To this day, Hester still has regular doctor visits to treat her immune system and every four weeks receives treatment at the University of Michigan to combat the effects

In addition to the iron, intravesical therapy (IVT) and myriad of medications Hester was administered by Dr. Fata, she recalled also receiving "huge quantities of things that I didn't need because they didn't co-exist with the labs and didn't add up and I shouldn't have been treated with these drugs."

"So, for three years I was treated unnecessarily to do harm, not to do no harm," Hester lamented of her ordeal with Fata.

Hester said in the office Fata “always got his way” and recalled him often petitioning her husband to convince her to accept his cancer treatments.

“As time went on, it was almost a ‘do-or-die’ attitude,” said Hester. “It was like, you’re going to die if you don’t do these treatments.”

She maintained that whenever she expressed her desire to end treatments, Fata would go as far as to bring up other patients who he claimed had just died from their own cancer.

“He always had a backdoor attitude,” said Hester. “I got caught up in this whole evil web.”

https://www.foxnews.com/entertainment/dr-death-podcast-patient-dr-farid-fata

First-trimester maternal serum biomarkers and the risk of cerebral palsy

Peris M, Reid SM, Dobie S, Bonacquisto L, Shepherd DA, Amor DJ. First-trimester maternal serum biomarkers and the risk of cerebral palsy. Dev Med Child Neurol. 2020 Nov 18. doi: 10.1111/dmcn.14732. Epub ahead of print. PMID: 33206412.

Abstract

Aim: To investigate whether combined first-trimester screening (cFTS) biomarkers are associated with cerebral palsy (CP) and to identify CP characteristics associated with abnormal biomarker levels. 

Method: In this retrospective case-control data linkage study, we matched mothers of 435 singletons with CP from a population register to their cFTS records and selected 10 singleton pregnancy controls per case. We compared mean and abnormal levels (expressed as multiples of the median [MoMs]) of pregnancy-associated plasma protein-A (PAPP-A), beta subunit of human chorionic gonadotrophin (β-hCG), and nuchal translucency between cases and controls and between CP subgroups. 

Results: Compared with control pregnancies, CP pregnancies had lower mean levels of PAPP-A (0.95 vs 1.01 MoM, p=0.02) and β-hCG (0.93 vs 0.99 MoM, p=0.02). Biomarker levels in CP pregnancies were 1.8 times more likely to be associated with abnormally low levels of PAPP-A (p<0.01), 1.4 times for β-hCG (p=0.12), and 2.6 times for low PAPP-A and β-hCG together (p=0.04). In cases with CP, an abnormally low PAPP-A level was associated with moderate preterm birth, low Apgar scores, and Gross Motor Function Classification System level V. Low β-hCG was associated with very low birthweight. 

Interpretation: Low first-trimester biomarker levels suggest a role for early pregnancy factors in some causal pathways to CP.

Courtesy of:  https://www.mdlinx.com/journal-summary/first-trimester-maternal-serum-biomarkers-and-the-risk-of-cerebral-palsy/4SsnM8kHtpOrX1kX57oRHW

Tuesday, November 24, 2020

Mother's email--child with CLN2

Today would have been his 82nd brineura treatment. We did not go today and won't be going to anymore. 5 years ago he was diagnosed and had 3 years of treatment. The crying/screaming has gotten really bad and it is everyday despite med changes and working with palliative care. It was a very emotional hard decision for me but I have to think about him and I'm not giving up, I'm just fighting harder for peace and comfort. I will forever be grateful for treatment and more time with him. Because of treatment he had so many great days, we love you all for everything you have done. Thank you so much. All our love,

Mom and son

Dangers of a medical board investigation

Cynthia H. Moran, MD, has a medical degree, a passion for treating the elderly, and a desire to work. What she doesn't have is a job or hopes of getting one anytime soon. 

The Houston physician has never been charged with a crime, but she did run afoul of the Texas Medical Board, an experience she said has left her destitute and virtually unemployable in the medical field. 

"By the time the board gets through with you, you will be bankrupt and have nothing," she said. 

Moran has a long, tangled history with the board involving self-prescribing, opioid abuse, depression, and unprofessional conduct. After years of license suspension, drug testing, additional CME, substance abuse treatment, and work restrictions, her supervision by the board ended in 2019, but she has been largely unable to find work as a physician. 

"I feel like a felon. I really understand what it's like to be someone who does their time but then can't get a job, can't get an apartment. It's in your record and there's nothing you can do about it," she said. 

Although Moran largely created her own troubles, her experience shows the power state medical licensing boards have when it comes to disciplining physicians. 

Reprimands to Revocations

Many physicians think of their state medical boards as simply the bodies that issue their medical licenses, but the boards have other functions, including investigating complaints against licensed medical professionals and, sometimes, disciplining them. 

According to 2017 statistics from the Federation of State Medical Boards (FSMB) (the most recent available), state boards took 8813 actions that year. These included 796 suspensions, 764 probations, 570 surrendered licenses, and 264 revoked licenses. 

Boards also can order doctors to enter state-run physician health plans to receive treatment for substance abuse, or they can allow physicians to practice only under the supervision of colleagues. 

Although they vary by state, the boards are fundamentally similar. Members are appointed by the governor. A majority of them are physicians, and the remainder are nonmedical professionals. Their investigators, often retired law enforcement officials, have broad powers to collect evidence, including medical records. Their authority is backed by the state attorney general. 

Although physicians tend to worry more about being sued for malpractice, a medical board investigation can be more worrisome, said William Sullivan, DO, JD, an emergency department physician and attorney in Illinois who has represented doctors before that state's board. Board disciplinary actions outnumber malpractice awards by four to one in that state, he estimated. 

"The gravity of this is something that many physicians don't understand," he said.

You Can Be the Subject of Anonymous Complaints and Investigations

Anyone can file a complaint against a physician with a state board. The grievances can be about anything from a crowded waiting room to physician impairment. 

Of course, the most trivial complaints (out-of-date magazines in the waiting room) are dismissed out of hand, but boards have the authority to investigate whatever it chooses. The most common investigations center around complaints of impairment, substance abuse, improper prescribing, faulty medical records, mental and physical health problems, and standard of care. Boards also will act if a physician is found guilty of a crime or misconduct unrelated to his or her medical practice. 

"There are a lot of ways doctors get into trouble," said Edward Dauer, MD, a radiologist who served on the Florida board for 11 years. 

Investigations often expand beyond their original scope into all aspects of a practice. "Once you're on their radar, they can find something," Sullivan said. 

All punitive actions taken by state boards are reported to the Department of Health and Human Services' National Practitioner Data Bank, which is accessible to all state boards. Sanctioned physicians who set up practice in another state often find that their new home has adopted the sanctions leveled by the original state, something boards can do without conducting their own investigations. 

"For doctors, discipline is forever. It never goes off your record," Dauer said. 

In addition, Medicare, Medicaid, and private insurers can exclude disciplined physicians, which can cripple a practice's finances. So what can doctors do to avoid problems with the boards? 

Don't Do Anything Wrong

That sounds glib and obvious, but many physicians get into trouble by unwittingly violating state medical regulations regarding such things as CME, insurance requirements, failure to notify the board of address changes, and personal relationships with current or former patients. 

"The best advice to avoid these issues is to do a Google search for the Medical Practice Act in the state in which they practice," said Sullivan. He noted that doctors should regularly check for changes in regulations. 

Keeping on good terms with colleagues and patients also helps, he said. He noted that many complaints stem from personal disputes and grievances. 

But what if a physician becomes the subject of an investigation? What should they do? 

Take Any Complaint Seriously

Too many physicians dismiss investigations initially. "Some people have the wrong idea that if they ignore it, it will go away. It won't go away," Sullivan said. 

Whether the initial contact comes through a letter or a visit from a board investigator, it should be treated with urgency. Ohio attorney Beth Collis said one client angrily scrawled one-word answers with a Sharpie on the questionnaire he was mailed — answers he was stuck defending throughout the rest of the investigation. Other doctors have ordered investigators out of their offices — another mistake. Failure to cooperate can result in an immediate license suspension. 

"They should be speaking to these investigators like they were talking to a highway patrolman on the side of the road. They hold all the cards," said Collis, who specializes in representing professionals before licensing boards. 

Some physicians mistakenly assume that because their state board is made up mostly of fellow doctors, they will be able to make a complaint go away with some collegial chat. 

Not so. "Medical board members see themselves as protecting the public. They're very punitive," Collis said. 

At one time, state boards might have been lax in their supervision of physicians, but that changed in the 1980s when the watchdog group Public Citizen began ranking state medical boards by how effective they were in policing doctors.

Public Citizen used FSMB data on serious disciplinary actions per 1000 doctors in each state to calculate its rankings, a practice that FSMB called incomplete and a misuse of its statistics. Nonetheless, the annual rankings generated a lot of publicity critical of state boards and might have spurred a tougher approach by regulators. 

Public Citizen stopped publishing its annual rankings in 2013 after FSMB ceased supplying the data, but the get-tough approach remains, lawyers said. 

About 95% of complaints are dismissed with nothing more serious than a letter to the doctor, but boards don't hesitate to act when the misconduct is serious, said Dauer, the former Florida board member. "I felt it was my obligation to protect the public," he said. 

Don't Try to Fix It Yourself

Although many complaints are anonymous, doctors can often figure out what or who it involves. Their impulse might be to contact a patient who complained, correct a medical record, or otherwise try to resolve the matter personally. 

It's better to leave things alone, the experts said. Don't contact a patient. Give the board access to whatever information it asks for, but don't alter anything, particularly medical records. "That's how you're going to get your license revoked," Dauer said. He noted that when doctors add notations to records, they must date them. 

Hire a Lawyer

Many physicians assume they can resolve the complaint easily by explaining themselves to the board or investigators, or they don't realize their license or practice could be at stake. 

They're better off letting a lawyer speak for them. Attorneys knowledgeable in this realm specialize in representing licensed professionals before regulatory boards and have the greatest knowledge of administrative law and how to negotiate the hearings and procedures. 

Typically, a hearing is held before a subcommittee of the board, which can recommend a settlement to the full panel. Cases in which a settlement is not reached can go before the entire board. 

Although full hearings can be similar to a trial, there are crucial differences regarding evidentiary rules and other matters, Collis said. For example, in Ohio, defendant physicians do not get to see the board's full case against them before the hearing, which can make preparing a defense difficult. And the standard for burden of proof is a preponderance of evidence, as in civil suits, not evidence beyond a reasonable doubt, as in a criminal trial. 

Cases that go to full hearings and beyond to appeals in state courts can take years to resolve, and a physician's license can be suspended for the duration. 

Get Help Before It's Too Late

Physicians looking for support and advice can turn to organizations such as the Coalition for Physician Rights (CPR), an organization formed in 2018 by Kernan Manion, MD, a former psychiatrist who was forced to deactivate his license after an investigation by the North Carolina medical board. 

CPR has advised hundreds of physicians, most of whom he said come to him once they realize they're in over their heads. "Almost everyone comes in too late," Manion said. "They're sitting ducks. They don't know how to respond." 

In addition to offering advice and support, CPR lobbies for reform in how boards operate. A number of states, including Oklahoma, have made reforms in recent years. 

The appointed boards are too reliant on their administration and staff and usually rubber-stamp disciplinary recommendations, Manion said. He also criticized the boards' lack of accountability: "A board operates without external or internal oversight. It is an autonomous entity operating on its own." 

As for Moran, the Houston doctor sanctioned by the board, at age 61, she's interviewing for physician jobs around the country, refusing to give up medicine. 

"What else can I do?" she said. "It's what I've done my entire life. It's what I went to school for. I don't know how to do anything else." 

James F. Sweeney is a freelance healthcare writer based in Cleveland, Ohio.

https://www.medscape.com/viewarticle/940672?

Monday, November 23, 2020

Current evidence on use of cannabis for headache disorders

In a special workshop at the 2020 Virtual Scottsdale Headache Symposium, the evidence for potential benefits and harm of Cannabis use in people with headache disorders was presented. There are known anti-inflammatory and analgesic effects of compounds found in Cannabis. In particular, tetrahydrocannabinol (THC) reduces inflammation twice as much as hydrocortisone and 20 times as much as aspirin. Cannabidiol (CBD), which is not psychoactive, has anti-inflammatory effects that are orders of magnitude higher than aspirin. The terpenes have both anti-inflammatory and analgesic properties. It is postulated that the combination of these compounds in Cannabis creates synergistic effects. 

According to the National Academies of Science, Engineering, and Medicine, "use of Cannabis to treat pain is supported by well-controlled clinical trials with conclusive or substantial evidence that Cannabis is an effective treatment for chronic pain in adults." The number needed to treat with cannabinoids for pain benefit is approximately 3.4. 

In the nervous system, the cannabinoid 1 (CB1) receptor is dense in the central nervous system (CNS) and peripheral nervous system (PNS). In the brainstem, CB1 receptors inhibit trigeminovascular responses of the A-delta and C-fibers, both implicated in the pathophysiology of headache, and activation of the CB1 receptor is modulated by the 5-HT1B/D receptors, the same receptors acted upon by triptans. 

For headache disorders, however, the data are limited to case series, case reports, surveys, retrospective review, and only 2 prospective trials with a control group. A small controlled study of cannabinoids (oral compound of 200 mg 0.4% THC/9% CBD in a 200 mL fat emulsion) for treatment of chronic migraine (n=48) and determined no effect at doses under 100 mg, and a 55% decrease in pain intensity with doses of 200 mg. For preventive treatment, amitriptyline 25 mg/day vs 200 mg of the THC/CBD compound reduced migraine headache days over 3 months by 40.4% and 40.1% respectively. Additional acute dosing was allowed and in those with chronic migraine, this decreased pain intensity by 43.5%. 

A randomized double-blind active-control crossover trial to treat people with medication-overuse headache (daily analgesia for at least 5 years with 3 detoxification attempts that failed the patient; n=30). The artificial cannabinoid nabilone compared with ibuprofen (each given for 8 weeks with 1-week washout in between and order randomized) reduced daily analgesic intake, medication dependence, and pain intensity. 

A survey study of 2,032 individuals in Canada using medical Cannabis showed that 25% were treating headache as their primary symptom and 88% of these people had a positive diagnosis of migraine. Of these individuals, 55% had substituted Cannabis for another treatment, including opiates, antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), antiseizure medications, and muscle relaxants. 

The importance of highlighting potential harms of Cannabis use with patients was also highlighted. Some of the features that point to misuse and abuse are using larger amounts than intended over a longer period than intended, cravings, wanting to stop but not being able to do so, and use in physically hazardous situations, such as while driving. It is important to note that approximately 1 in 10 Cannabis users develop substance abuse disorder. Side effects can also occur, including increased heart rate, changes to breathing rate, increased appetite, dry mouth, sleepiness, impaired cognition, and impaired coordination. Impaired driving ability is of particular importance.

https://practicalneurology.com/news/current-evidence-on-use-of-cannabis-for-headache-disorders

Thursday, November 19, 2020

A proposed diagnostic algorithm for inborn errors of metabolism presenting with movement disorders.

Juan Darío Ortigoza-Escobar.  A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders. Published on 13 November 2020.  Front. Neurol. doi: 10.3389/fneur.2020.582160

Inherited metabolic diseases or inborn errors of metabolism frequently manifest with both hyperkinetic (dystonia, chorea, myoclonus, ataxia, tremor, etc.) and hypokinetic (rigid-akinetic syndrome) movement disorders. The diagnosis of these diseases is in many cases difficult, because the same movement disorder can be caused by several diseases. Through a literature review, two hundred and thirty one inborn errors of metabolism presenting with movement disorders have been identified. Fifty-one percent of these diseases exhibits two or more movement disorders, of which ataxia and dystonia are the most frequent. Taking into account the wide range of these disorders, a methodical evaluation system needs to be stablished. This work proposes a six-step diagnostic algorithm for the identification of inborn errors of metabolism presenting with movement disorders comprising red flags, characterization of the movement disorders phenotype (type of movement disorder, age and nature of onset, distribution and temporal pattern) and other neurological and non-neurological signs, minimal biochemical investigation to diagnose treatable diseases, radiological patterns, genetic testing and ultimately, symptomatic, and disease-specific treatment. As a strong action, it is emphasized not to miss any treatable inborn error of metabolism through the algorithm. 


Figure 3. Radiological patterns in selected inborn errors of metabolism. (A) Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1). MRI (T2W) showing bilateral symmetric signal hyperintensity in globus pallidus and a small cavitation in the left globus pallidus. (B) Type 3 Gaucher disease (GBA). MRI (T1W) showing decrease volume of white matter and hydrocephalus. (C) Glutaric aciduria type 1 (GCDH). MRI (T2 FSE) showing bilateral symmetric signal hyperintensity in putamen and globus pallidus and posterior periventricular white matter abnormalities. (D) Rhizomelic chondrodysplasia punctata, type 1 (PEX7). MRI (T2) showing bilateral symmetric posterior periventricular white matter hyperintensity and ventriculomegaly. (E,F) L-2-hydroxyglutaric aciduria (L2HGA). MRI (T2 and FLAIR) showing bilateral diffuse cerebral white matter and dentate nuclei hyperintensities. (G) Methylmalonic aciduria and homocystinuria, cblC type (MMACHC). MRI (T1) showing a very thin corpus callosum. (H) Aicardi-Goutières syndrome 2 (RNASEH2B). CT showing multiple calcifications in basal ganglia.


Wednesday, November 18, 2020

Thank you pediatric medical professionals, as we fondly bid you adieu

As the mother of a child born with hypoplastic left heart syndrome, besides going through four open-heart surgeries and coding, my son has also had eight abdominal surgeries, including a Ladd’s procedure and resection of his colon.  William also functions without his appendix, spleen, and gall bladder. In addition to every kind of therapy imaginable, he has had to endure pamidronate infusions, daily shots, G-tube feedings, and TPN. Who knows how many times he’s been X-rayed and poked by a needle. It’s been a roller coaster, but he wouldn’t be here without you: all of you.

Our thank you list includes the amazing skill and care from his doctors and nurses.  However, his team of health care professionals is so much more. It includes the speech, respiratory and physical therapists, the X-ray and lab technicians, and the foodservice staff. It includes the child life and art therapists, the tutors, home health coordinators, and chaplains. It also includes the often left-out cleaning personnel who cleaned our rooms day after day, always reminding us to “be careful not to slip on the floor.”

Each of you in the field of pediatric medicine has many William’s in your professional life. So, while all of you are exhausted from being stretched and pulled right now, I want to thank you for saving the William’s of the world. You are impacting them more than just through your training.  How you look at them and listen to them makes a difference.  Your William’s are studying you and watching your every move.  They know when you are frustrated, tired, and unsure of what to do next.  They celebrate with you when things are going well and they feel your concern when they aren’t.  I believe they are deeply connected to every one of you.  They may forget some of your names, but they know what you have done for them.

My William will be turning 20 years old on December 4th.  He’s a sophomore at the University of Nebraska and is majoring in emergency management, with a minor in journalism.  He wants to help people in trouble – just like all of you have done for him. “Mom, I want to help people on their worst day,” said William recently.

We are more than a little nervous about leaving the security and comfort of your pediatric world behind. Still, to all of you amazing pediatric health professionals, it is because of your expertise and the dedication to your calling, we can say thank you and adieu. May you continue doing for children what you have done for us knowing your impact is deep and will never be forgotten.

https://www.kevinmd.com/blog/2020/11/thank-you-pediatric-medical-professionals-as-we-fondly-bid-you-adieu.html

  

Bilateral perisylvian polymicrogyria and wrongful life

A federal judge in Seattle has awarded $10 million to the family of a severely disabled child who was born after a community clinic nurse inadvertently gave the mother a flu shot instead of a birth-control injection.

The Seattle Times reported that U.S. District Judge Robert Lasnik last week awarded the child $7.5 million for her medical, educational and other expenses, on top of $2.5 million in damages for her parents.

After a trial earlier this year, Lasnik found that the mother, Yeseni Pacheco, did not want to become pregnant and would not have become pregnant in 2011 if the nurse at the Neighborcare Health clinic had given her the correct shot.

The federal government is responsible for the damages because the clinic, which serves low-income and uninsured patients, is federally funded.

The family’s lawyers, Mike Maxwell and Steve Alvarez, described the case in court documents as a “wrongful pregnancy” and “wrongful life” case. They said the case was a hard-fought battle and sharply criticized the government for refusing to accept responsibility at the outset.

“Luis and Yesenia Pacheco are pleased that they’re closer to receiving the funds needed for their daughter’s extraordinary medical care and training,” they wrote in a statement. “It was a long hard road for the family.”

Emily Langlie, a spokeswoman for the U.S. Attorney’s Office in Seattle, which defended the lawsuit, said some of the delays were necessary to ensure medical experts could accurately measure the extent of the child’s disabilities.

Pacheco, an El Salvadoran refugee who moved to the U.S. when she was 16, had gone to the clinic for a quarterly injection of Depo-Provera, a hormone used for birth control.

A nurse at the clinic who had been administering walk-in flu shots all day apparently did not check Pacheco’s chart and gave Pacheco the flu vaccine instead, the court found.

Pacheco didn’t discover the mistake until she called to make her next appointment, more than two months later. By then, she was pregnant.

The child is now 8 years old and in third grade at an Everett-area school, north of Seattle.

According to court documents, she suffers from a birth defect known as bilateral perisylvian polymicrogyria (PMG), which has resulted in cognitive delays, slowed speech and language skills, epilepsy, vision problems and other complications.

She has an IQ of 70, according to the family’s attorneys. Maxwell said that she will live a normal life span, and will require some level of care and assistance for her entire life. 

Justice Department lawyers are asking that some of the award be placed in a “reversionary trust” that would return to the government if the girl does not need it.

https://www.foxnews.com/health/judge-awards-10-million-family-wrongful-life-case

Bumetanide to treat neonatal seizures

Soul JS, Bergin AM, Stopp C, Hayes B.  Singh A, Rosa Fortuno C, O'Reilly D, Krishnamoorthy K, Jensen FE.  Rofeberg V, Dong M, Vinks A, Wypij D, Staley K for the Boston Bumetanide Trial Group. A pilot randomized, controlled, double‐blind trial of bumetanide to treat neonatal seizures. Controlled bumetanide trial for neonatal seizures. Annals of Neurology |November 18, 2020

In the first trial to include a standard‐therapy control group, this study was undertaken to investigate bumetanide added to phenobarbital to treat neonatal seizures. Researchers randomized individuals with EEG‐confirmed seizures after ≥ 20 and < 40 mg/kg phenobarbital to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Individuals were assigned randomly to treatment (n=27) and control (n=16) groups. This randomized, controlled, multicenter trial indicated a drop in seizure burden that can be attributed to bumetanide over phenobarbital with no increase in serious adverse effects. Definitive proof of efficacy needs an appropriately powered phase 3 trial, and further evaluations of bumetanide and other drugs should include a control group and balance seizure severity.

Courtesy of:  https://www.mdlinx.com/journal-summary/a-pilot-randomized-controlled-double-blind-trial-of-bumetanide-to-treat-neonatal-seizures-controlled/27pSoiGDTvSo85KsZSqAkg

Thursday, November 12, 2020

Perampanel potpourri

Santamarina E, Bertol V, Garayoa V, García-Gomara MJ, Garamendi-Ruiz I, Giner P, Aranzábal I, Piera A, Arcos C, Esteve P, Marinas A, García-Escrivá A, Viloria-Alebesque A, Loro FA, de Tienda AP, Olivan JA, Bonet M, Dávila-González P, Sivera R, Molins A, Sansa G, Roche JC, Martínez AB, Monteagudo S, Casadevall T. Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs. Seizure. 2020 Oct 7;83:48-56. doi: 10.1016/j.seizure.2020.09.026. Epub ahead of print. PMID: 33096456.

Abstract

Purpose: To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD).

Methods: This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. 

Results: Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. 

Conclusion: PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Courtesy of:  https://www.mdlinx.com/journal-summary/efficacy-and-tolerability-of-perampanel-as-a-first-add-on-therapy-with-different-anti-seizure-drugs/6hwYqmakG7fl145wzGPfvK

Santamarina E, Alpuente A, Maisterra O, Sueiras M, Sarria S, Guzman L, Abraira L, Salas-Puig J, Toledo M. Perampanel: A therapeutic alternative in refractory status epilepticus associated with MELAS syndrome. Epilepsy Behav Case Rep. 2019 Feb 7;11:92-95. doi: 10.1016/j.ebcr.2019.01.008. PMID: 30834194; PMCID: PMC6384302.

Abstract

To our knowledge, there are no reports of status epilepticus (SE) associated with mitochondrial diseases and treated with perampanel (PER). We present three cases of patients with refractory SE associated with MELAS syndrome who responded favorably to PER. All cases were diagnosed as non-convulsive SE (focal without impairment of level of consciousness). After an initial treatment with other anti-seizure drugs, PER was added in all cases (8, 16 and 12 mg) and cessation of SE was observed within the next 4-8 hours. All the cases involved a stroke-like lesion present on brain MRI. In our patients, PER was an effective option in SE associated with MELAS syndrome. 

Santamarina E, Sueiras M, Lidón RM, Guzmán L, Bañeras J, González M, Toledo M, Salas-Puig X. Use of perampanel in one case of super-refractory hypoxic myoclonic status: Case report. Epilepsy Behav Case Rep. 2015 Aug 8;4:56-9. doi: 10.1016/j.ebcr.2015.06.007. PMID: 26286206; PMCID: PMC4536289.

Abstract

Proper treatment of hypoxic myoclonic status is not clearly determined. Induced hypothermia is improving prognosis and a more aggressive treatment might be beneficial in some patients. Among the new options of antiepileptic drugs, perampanel (PER) is a drug with a novel mechanism, and it might be a promising drug for myoclonic status or as an antimyoclonic drug. We describe the use of PER in one patient with hypoxic super-refractory myoclonic status. 

Description: A 51-year-old patient presented after an out-of-hospital cardiac arrest due to an acute myocardial infarction. The patient was diagnosed with clinical and electrical (EEG) myoclonic status at the rewarming phase. Several treatments were used, starting with clonazepam, valproate, sedation (midazolam, propofol), and subsequently barbiturate-induced coma with persistent myoclonic status. Finally, we decided to try PER (dose: 6-8 mg) through a nasogastric tube, resulting in a marked improvement of EEG activity and myoclonus decrease. The patient had a progressive clinical improvement, with a CPC (Cerebral Performance Category) scale score of 1. 

Conclusion: This case shows the potential utility of PER as a therapeutic option in super-refractory hypoxic status and even its potential use before other aggressive alternatives considering their greater morbidity.

Wednesday, November 11, 2020

Cerebro-oculo-facio-skeletal syndrome and ERCC5 mutation

Inspired by a patient

Le Van Quyen P, Calmels N, Bonnière M, Chartier S, Razavi F, Chelly J, El Chehadeh S, Baer S, Boutaud L, Bacrot S, Obringer C, Favre R, Attié-Bitach T, Laugel V, Antal MC. Prenatal diagnosis of cerebro-oculo-facio-skeletal syndrome: Report of three fetuses and review of the literature. Am J Med Genet A. 2020 May;182(5):1236-1242. doi: 10.1002/ajmg.a.61520. Epub 2020 Feb 13. PMID: 32052936.

Abstract

Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare autosomal recessive neurodegenerative disease belonging to the family of DNA repair disorders, characterized by microcephaly, congenital cataracts, facial dysmorphism and arthrogryposis. Here, we describe the detailed morphological and microscopic phenotype of three fetuses from two families harboring ERCC5/XPG likely pathogenic variants, and review the five previously reported fetal cases. In addition to the classical features of COFS, the fetuses display thymus hyperplasia, splenomegaly and increased hematopoiesis. Microencephaly is present in the three fetuses with delayed development of the gyri, but normal microscopic anatomy at the supratentorial level. Microscopic anomalies reminiscent of pontocerebellar hypoplasia are present at the infratentorial level. In conclusion, COFS syndrome should be considered in fetuses when intrauterine growth retardation is associated with microcephaly, arthrogryposis and ocular anomalies. Further studies are needed to better understand XPG functions during human development.

Ferri D, Orioli D, Botta E. Heterogeneity and overlaps in nucleotide excision repair disorders. Clin Genet. 2020 Jan;97(1):12-24. doi: 10.1111/cge.13545. Epub 2019 Apr 22. PMID: 30919937.

Abstract

Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletal-syndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease-like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (ERCC3/XPB, ERCC2/XPD, ERCC5/XPG, ERCC1 and ERCC4/XPF) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype-phenotype relationships. Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed.

 

The phenotype and genotype of congenital myopathies based on a large pediatric cohort

Daniel Natera-de Benito. Carlos Ortez. Cristina Jou. Cecilia Jimenez-Mallebrera. Anna Codina, Laura Carrera-García, Jessica Expósito-Escudero, Sergi Cesar, Loreto Martorell, Pia Gallano, Lidia Gonzalez-Quereda, Daniel Cuadras, Jaume Colomer, Delia Yubero, Francesc Palau,  3Andres Nascimento .  The phenotype and genotype of congenital myopathies based on a large pediatric cohort. Pediatric Neurology. Published:November 05, 2020 DOI:https://doi.org/10.1016/j.pediatrneurol.2020.11.002 

Abstract

Background

Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts and the relationship between phenotypes and genotypes is only partially understood.

Methods

Retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological and molecular characterization of 104 patients with CM is reported.

Results

The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild grade (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with “specific” histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65/104 patients (62%), with RYR1 (24/104) and TTN (8/104) as the most frequent causative genes . Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in 1/3 patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%.

Conclusions

This study provides an updated picture of the clinical, histopathological and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy is significantly associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.

Courtesy of:  https://www.mdlinx.com/journal-summary/the-phenotype-and-genotype-of-congenital-myopathies-based-on-a-large-pediatric-cohort/5b7xsqETeovgSLVxn4vZt3

GDF-15 Is elevated in children with mitochondrial diseases

Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodríguez MA, Ramos F, Nascimento A, Ortez CI, Campistol J, Perez-Dueñas B, O'Callaghan M, Pineda M, Garcia-Cazorla A, Oferil JC, Montoya J, Ruiz-Pesini E, Emperador S, Meznaric M, Campderros L, Kalko SG, Villarroya F, Artuch R, Jimenez-Mallebrera C. GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016 Feb 11;11(2):e0148709. doi: 10.1371/journal.pone.0148709. Erratum in: PLoS One. 2016;11(5):e0155172. PMID: 26867126; PMCID: PMC4750949.

Abstract

Background: We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. 

Methods: We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. 

Results: Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3% (81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. 

Conclusions: Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels.

Thursday, November 5, 2020

Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy

Innes S, Laughton B, van Toorn R, Otwombe K, Liberty A, Dobbels E, Violari A, Kruger M, Cotton MF. Recovery of HIV encephalopathy in perinatally infected children on antiretroviral therapy. Dev Med Child Neurol. 2020 Nov;62(11):1309-1316. doi: 10.1111/dmcn.14639. Epub 2020 Aug 10. PMID: 32779195.

Abstract

Aim: To describe the trajectory of clinical signs in children who developed human immunodeficiency virus encephalopathy (HIVE) after starting early antiretroviral therapy (ART). 

Method: This was a retrospective case-cohort description of HIVE among Cape Town participants from the Children with HIV Early AntiRetroviral treatment (CHER) trial. Criteria for HIVE diagnosis were at least two of: (1) acquired central motor deficit, (2) impaired brain growth, and (3) failure to attain or loss of developmental milestones in the absence of an alternative aetiology. 

Results: Of 133 surviving participants who initiated ART at a median age of 9 weeks and who were followed until a median age of 6 years, 20 (12%) developed HIVE at a median age 31 months (interquartile range 19-37). In these, the first neurological deterioration was noticed at a median age of 19 months, when 16 were on ART and nine had undetectable HIV viral load for a median of 12 months. Signs of upper motor neurons were present in 18, of whom 12 resolved and four had persistent spastic diplegia; 19 had motor delay, of whom 14 resolved; 12 had language delay, of whom 11 resolved; and 16 had impaired brain growth, of whom only five recovered. For the 16 participants already on ART at HIVE diagnosis, regimens were not altered in response to diagnosis. 

Interpretation: HIVE may occur despite early ART initiation and virological suppression and then resolve on unchanged ART, most likely as intrathecal inflammation subsides. 

What this paper adds: Despite suppressive antiretroviral therapy, children can develop human immunodeficiency virus encephalopathy, The most common manifestations are motor deficits and impaired brain growth. Most experience improvement, with many resolving without additional intervention.

Courtesy of:  https://www.mdlinx.com/journal-summary/recovery-of-hiv-encephalopathy-in-perinatally-infected-children-on-antiretroviral-therapy/7ANppHSat0m4eADONpAsj7

Tuesday, November 3, 2020

CGRP monoclonal antibody use for the preventive treatment of refractory headache disorders in adolescents

Kaitlin A. Greene, Carlyn Patterson Gentile, Christina L. Szperka, Marcy Yonker, Amy A. Gelfand,Barbara Grimes, Samantha L. Irwin.  CGRP Monoclonal Antibody use for the Preventive Treatment of Refractory Headache Disorders in Adolescents.  Pediatric Neurology October 05, 2020  DOI: https://doi.org/10.1016/j.pediatrneurol.2020.09.014 

Abstract:

Background

Monoclonal antibodies (mAbs) to calcitonin gene-related peptide (CGRP) or its receptor have clinical trial evidence in adults with headache, but data are lacking in adolescents.

Objective

To describe the safety and efficacy of CGRP monoclonal antibody (mAb) treatment in adolescents with chronic headache disorders.

Methods

Retrospective multi-site cohort study of adolescents <18 years prescribed a CGRP mAb for headache prevention. Demographics, baseline headache characteristics, efficacy and side effect data was collected.

Results

n=112 adolescents received ≥1 dose of a CGRP mAb. Mean (SD; range) age at first dose was 15.9 years (1.4; 10.3 to 17.8). Ninety-four (83.9%) had chronic migraine, 12 (10.7%) had NDPH, and 6 (5.4%) had PPTH. At baseline, mean (SD) baseline headache days per month was 26.9 (6.1) (n=109) and headache was continuous in 75/111 (67.6%). At follow-up visit 1 there was a significant reduction in headache frequency compared to baseline (-2.0 days, 95% CI: -0.8 to -3.2). Significant benefit was perceived by 29.5% at follow-up visit 1 (n=33/112) and 30.1% (n=22/73) at visit 2. Significant functional improvement was perceived by 31% (n =31/94) at the 1st follow-up and 22.4% (n=15/67) at the 2nd follow-up. Most common side effects were injection site reactions in 17.0% (n=19) and constipation in 8.0% (n=9). Five patients (4.5%) discontinued due to side effects.

Conclusions

Side effects with CGRP mAb treatment in adolescents are similar to those reported in adult trials. CGRP monoclonal antibody treatment appears to benefit a proportion of adolescents with chronic refractory headache disorders

Courtesy of:  https://www.mdlinx.com/journal-summary/cgrp-monoclonal-antibody-use-for-the-preventive-treatment-of-refractory-headache-disorders-in/13F4pA17zrii3L00uViXJh

Troponin T correlates with MRI results in neonatal encephalopathy

Sweetman DU, Kelly L, Hurley T, Onwuneme C, Watson RWG, Murphy JFA, Slevin M, Donoghue V, Molloy EJ. Troponin T correlates with MRI results in neonatal encephalopathy. Acta Paediatr. 2020 Apr 13. doi: 10.1111/apa.15255. Epub ahead of print. PMID: 32281692.

Abstract

Aim: Troponin is a sensitive marker of asphyxia in term infants mirroring the myocardial injury sustained in global hypoxia-ischaemia. In addition, troponin is a sensitive marker of severity of stroke in adults and neonatal encephalopathy (NE). We aimed to examine the relationship between troponin T in infants with perinatal asphyxia and brain injury on MRI and correlate with neurodevelopmental outcome. 

Methods: Serum troponin was sampled in infants requiring resuscitation at birth and/or neonatal encephalopathy in a tertiary referral neonatal centre. Birth history, clinical parameters, neuroimaging and developmental outcome (Bayley Scores of Infant Development [BSID] III) were evaluated. 

Results: Infants with perinatal asphyxia (n = 54) had serum troponin T measured and 27 required therapeutic hypothermia. Troponin T levels on days 1 and 2 were predictive of need for TH, development of seizures and grade II/III NE (AUC = 0.7; P-values < .001), troponin T levels on days 1, 2 and 3 were highly significant predictors of mortality (AUC = 0.99, P-values .005). The cut-off values of troponin T for best prediction of mortality were 0.84, 0.63 and 0.58 ng/mL on days 1, 2 and 3, respectively. Troponin T on day 3 of life was predictive of injury in the combined area of basal ganglia/watershed on MRI (AUC 0.70; P-value = .045). 

Conclusion: Infants with brain injury on neuroimaging following perinatal asphyxia had significantly elevated serum troponin, and troponin also correlated with developmental scores at 2 years. Further studies combining troponin and MRI may assist in the classification of neonatal brain injury to define aetiology, prognosis and response to treatment.

Courtesy of:  https://www.mdlinx.com/journal-summary/troponin-t-correlates-with-mri-results-in-neonatal-encephalopathy/2gbTISJUqNNNWh7MOgXEjU