Our records of the human genome may still be missing tens of thousands of 'dark' genes. These hard-to-detect sequences of genetic material can code for tiny proteins, some involved in disease processes like cancer and immunology, a global consortium of researchers has confirmed.
They may explain why past estimates of our genome's size were way larger than what the Human Genome Project discovered 20 years ago.
The new international study, still awaiting peer review, shows our library of human genes very much continues to be a work in progress, as more subtle genetic features are picked up with advances in technology, and as continued exploration uncovers gaps and errors in the record.
These overlooked genes have been hiding away in regions of our DNA thought not to code for proteins. These regions were once dismissed as 'junk DNA' but it turns out small bits of these sequences are still being used as instructions for mini-proteins.
Institute of Systems Biology proteomicist Eric Deutsch and colleagues found a large cache of them by searching genetic data from 95,520 experiments for fragments of protein-coding sequence. These include studies using mass spectrometry to investigate small proteins, as well as catalogues of protein snippets detected by our own immune systems.
Instead of the long, well-known codes that initiate the reading of DNA instructions for protein creation, indicating the starting point of a gene, these 'dark' genes are preceded by shorter versions which have allowed them to be overlooked by scientists.
Despite these missing parts in their start sequences, the non-canonical open reading frame (ncORF) genes are still used as a template to create RNA and some of those are then used to make small proteins with only a handful of amino acids. Previous studies have shown cancer cells contain hundreds of such tiny proteins.
"We believe the identification of these newly-confirmed ncORF proteins is immensely important," the team writes in their paper. "Their proteins… may have direct biomedical relevance, which is manifested in the growing interest in targeting such cryptic peptides with cancer immunotherapy, including cellular therapies and therapeutic vaccines."
Some of the genes that encode these cryptic peptides are transposons that move around our genomes, including sequences inserted into us by viruses.
Others are what the researchers call aberrant. For example, some of the proteins known to exist from mass spectrometry evidence have only ever been located in cancer samples, so their associated genes may not naturally belong in our bodies.
"Thus, it remains possible that certain ncORF peptides reflect aberrant proteins whose existence is deemed out of context with the canonical proteome," Deutsch and team explain.
Out of the 7,264 sets of these non-canonical genes identified, the researchers found at least a quarter of them could create proteins. This amounted to at least 3,000 new peptide-coding genes to add to the Human Genome, and the team suspects there are tens of thousands more, all missed by previous proteomic techniques.
"It's not every day that you get to open a research direction and say, 'We might have a whole new class of drug targets for patients,'" University of Michigan neurooncologist John Prensner told Elizabeth Pennisi at Science.
The tools the team have developed will help other researchers to continue to uncover more of this dark genetic matter.
This research is awaiting peer review on bioRxiv.
https://www.sciencealert.com/dark-genes-hiding-unseen-in-human-dna-have-just-been-revealed
It was barely a generation ago – during the spring of 2003, in fact – when scientists at The Human Genome Project completed their work sequencing the human genome.
But even for the world’s leading geneticists, the ‘Book of Life’ is a heavy read. Researchers are still making sense of it.
It was a landmark moment, of course, not just in science, but in life on Earth – the first time an organism catalogued the very building blocks that it’s made of. It sparked the genetic revolution that we’re currently living through, but it also raised some serious questions.
Questions like, ‘Why is there so much of it?’
One of the strange and startling things about the completed human genome was how little of it seemed to be doing anything. There are around three billion nucleotide pairs in the human genome (the ‘letters’ in our DNA: A, C, G and T).
Less than two per cent of those (around 20,000) represent protein-encoding genes that give the cells in our bodies their marching orders. So, what’s the rest of it doing?
Some called it junk DNA. Genetic gibberish – a pile of leftovers from millions of years of evolution or an impossible word search where very little makes sense.
And it seems that at least some of it is indeed non-functioning. But not all of it.
Scientists are beginning to shed light on this dark matter of the human genome. Far from a junk heap, it performs a crucial regulatory or modifying function for the protein-encoding genes. Some have likened these DNA sequences to volume-control buttons for how our genes are expressed.
For example, enhancer sequences increase the transcription of genes from DNA to RNA. Silencers do the reverse.
Large swathes of the dark genome are also made up of long, repetitive sequences of DNA known as transposons.
These too play a critical role in the way our genes are expressed, and they’re linked to momentous evolutionary steps and our ability to adapt to our environments.
Also known as ‘jumping genes’, transposons can move from one section of a genome to another. This ability can trigger seismic genetic mutations and reversals.
Scientists believe, for example, that transposons are linked to the development of opposable thumbs in humans and the loss of tails in our species and other great apes.
They may also be responsible for tumour development in some circumstances, as well as certain hereditary diseases. Haemophilia and Duchenne muscular dystrophy are two examples thought to arise from repetitive DNA sequences linked to transposons.
That’s just one reason why the dark genome is now a hotbed of medical research. Scientists hope that in the next two decades, our growing understanding of these once-ignored chapters from the ‘Book of Life’ will lead to a new generation of therapies for treating genetic disorders.
This article is an answer to the question (asked by Asa Mcintyre, via email) 'If genes only make up around two per cent of our DNA, What makes up the other 98 per cent?'
https://www.sciencefocus.com/the-human-body/dark-dna
One of our strongest defenders in the battle against cancer is a gene called p53, known in the science world as “the guardian of the genome.” It’s the most important of several “tumor suppressors” that keep us safe by controlling cell division, repairing DNA damage and destroying abnormal cells. This gene is so important that in most cancers, it’s the one most likely to be disabled, often due to mutations, or changes, in DNA. Mutations can cause cells to behave abnormally. Sometimes they can even transform p53 from a protective gene into an oncogene, causing it to switch sides in the battle so that it can actually help the cancer grow.
A decade ago, research revealed a previously unknown way that non-mutated p53 protects us from cancer. Led by Andrei Gudkov, PhD, DSci, Senior Vice President of Research Technology and Innovation and the Garman Family Chair in Cell Stress Biology at Roswell Park Comprehensive Cancer Center, a team of scientists first demonstrated that p53 also silences, or suppresses, genetic elements called retrotransposons. About 40% of our DNA is made up of millions of copies of retrotransposons, often referred to as the “dark genome.”
Technically, retrotransposons are viruses that entered human DNA in the far-distant past and underwent several explosive expansions. In normal cells they’re inactive, hidden behind a dense layer of proteins. “They’re asleep in the DNA of our normal cells,” explains Dr. Gudkov.
But they become active in tumor cells, and like all viruses, they’re laser-focused on one thing: making copies of themselves. They insert those copies into places in our DNA where they don’t belong. “This process is very dangerous, because they can disrupt important genes in the new places they enter and cause other forms of DNA damage,” says Dr. Gudkov. “This can change the genetic program of cells and create new kinds of cells that can become cancerous. Cells with activated retrotransposons are like cells that contain a piece of uranium or radium.”
Thanks to that discovery by Dr. Gudkov’s lab — and follow-up work in his and other labs — today p53 is acknowledged as a silencer of the dark genome. While other control mechanisms also help keep the dark genome in check, p53 is especially important to that effort — and things go haywire when it’s unable to do its job. “In the absence of p53, the risk of the retrotransposons awakening increases dramatically,” says Dr. Gudkov.
Although p53 has great potential for preventing cancer, so far it has been impossible to develop drugs that would restore its lost function in tumor cells. But, the discovery that p53 acts as a silencer of retrotransposons provided a new opportunity to solve that puzzle.
Dr. Gudkov and his colleagues came up with the idea of using a drug that could serve as a substitute for the disabled p53 gene and take over its job of silencing the retrotransposons. Retrotransposons replicate themselves using a process called reverse transcription, which relies on an enzyme called reverse transcriptase. It’s the same process used by HIV — the virus that causes AIDS — to replicate itself. Drugs called reverse transcriptase inhibitors, which block the HIV replication process, are essential ingredients in “drug cocktails” that keep the disease under control.
“Some of these drugs appeared to be quite effective ,” explains Dr. Gudkov. “This gave us the idea of repurposing those anti-HIV drugs to use in cancer cells in which retrotransposons are awake and actively expanding, to suppress the process and thereby partially restore p53 function.”
Studies conducted by Dr. Gudkov and his team went on to prove that the strategy works in preclinical models, dramatically extending remission time after chemotherapy. “Based on this result, we initiated a clinical trial at Roswell Park for people with one of the most challenging cancers — small cell lung cancer. We hope we can extend their life by extending the time of remission.”
Currently underway at Roswell Park under the direction of medical oncologist and lung cancer expert Grace Dy, MD, the study will enroll approximately 30 patients, who will receive standard treatment along with an anti-HIV drug to hit cancer with a one-two punch. Researchers at another U.S. cancer center have adopted the same approach in a study for patients with late-stage colorectal cancer, and the encouraging results have demonstrated its potential role in cancer therapy.
“This could provide a fantastic opportunity for improving any given cancer treatment by making it more reliable, with drugs we already have in place and simply need to repurpose from one disease to another,” says Dr. Gudkov.
Dark genome research may point to better screening and treatment options
Additional insight into the dark genome grew from other recent research led by Dr. Gudkov and his colleagues, who showed that humans can develop an immune response against retrotransposons, generating high levels of antibodies against their encoded proteins. This response is especially strong in some patients with lung, pancreatic, ovarian, liver and esophageal cancer, which are among the deadliest cancers. Often called “silent killers,” they usually don’t cause symptoms until the disease has progressed to the late stages, when a cure is far less likely. But antibodies against retrotransposons can be detected in the blood of these patients even in the early stages and could serve as a red flag to indicate the presence of disease when it’s more treatable.
“This discovery sets the stage for the development of improved diagnostics and immunotherapies for these challenging cancers,” says Dr. Gudkov.
What’s ahead? “If we could create immunotherapies directed at the cells linked to retrotransposons, it would mark a significant breakthrough in the prevention and treatment of various types of cancer,” says Dr. Gudkov. “This is a long road, but we’re on the way.”
https://www.roswellpark.org/cancertalk/202409/outsmarting-dark-side-our-dna
Wednesday, November 27, 2024
Concussions slow brain activity of high school football players
Radiological Society of North America. "Concussions slow brain activity of high school football players." ScienceDaily. ScienceDaily, 27 November 2024. <www.sciencedaily.com/releases/2024/11/241127004157.htm>.
A new study of high school football players found that concussions affect an often-overlooked but important brain signal. The findings are being presented next week at the annual meeting of the Radiological Society of North America (RSNA).
Reports have emerged in recent years warning about the potential harms of youth contact sports on developing brains. Contact sports, including high school football, carry a risk of concussion. Symptoms of concussion commonly include cognitive disturbances, such as difficulty with balancing, memory or concentration.
Many concussion studies focus on periodic brain signals. These signals appear in rhythmic patterns and contribute to brain functions such as attention, movement or sensory processing. Not much is known about how concussions affect other aspects of brain function, specifically, brain signals that are not rhythmic.
"Most previous neuroscience research has focused on rhythmic brain signaling, which is also called periodic neurophysiology," said study lead author Kevin C. Yu, B.S., a neuroscience student at Wake Forest University School of Medicine in Winston-Salem, North Carolina. "On the other hand, aperiodic neurophysiology refers to brain signals that are not rhythmic."
Aperiodic activity is typically treated as 'background noise' on brain scans, but recent studies have shown that this background noise may play a key role in how the brain functions.
"While it's often overlooked, aperiodic activity is important because it reflects brain cortical excitability," said study senior author Christopher T. Whitlow, M.D., Ph.D., M.H.A., Meschan Distinguished Professor and Enterprise Chair of Radiology at Wake Forest University School of Medicine.
Cortical excitability is a vital part of brain function. It reflects how nerve cells, or neurons, in the brain's cortex respond to stimulation and plays a key role in cognitive functions like learning and memory, information processing, decision making, motor control, wakefulness and sleep.
To gain a better understanding of brain rhythms and trauma, the researchers sought to identify the impacts of concussions on aperiodic activity.
Pre- and post-season resting-state magnetoencephalography (MEG) data was collected from 91 high school football players, of whom 10 were diagnosed with a concussion. MEG is a neuroimaging technique that measures the magnetic fields that the brain's electrical currents produce.
A clinical evaluation tool for concussions called the Post-Concussive Symptom Inventory was correlated with pre- and post-season physical, cognitive and behavioral symptoms.
High school football players who sustained concussions displayed slowed aperiodic activity. Aperiodic slowing was strongly associated with worse post-concussion cognitive symptoms and test scores.
Slowed aperiodic activity was present in areas of the brain that contain chemicals linked with concussion symptoms like impaired concentration and memory.
"This study is important because it provides insight into both the mechanisms and the clinical implications of concussion in the maturing adolescent brain," said co-lead author Alex I. Wiesman, Ph.D., assistant professor at Simon Fraser University in Burnaby, British Columbia, Canada. "Reduced excitability is conceptually a very different brain activity change than altered rhythms and means that a clear next step for this work is to see whether these changes are related to effects of concussion on the brain's chemistry."
The results highlight the importance of protective measures in contact sports. The researchers cautioned that young players should always take the necessary time to fully recover from a concussion before returning to any sport.
The findings from the study may also influence tracking of post-concussion symptoms and aid in finding new treatments to improve recovery.
"Our study opens the door to new ways of understanding and diagnosing concussions, using this novel type of brain activity that is associated with concussion symptoms," Dr. Whitlow said. "It highlights the importance of monitoring kids carefully after any head injury and taking concussions seriously."
Other co-authors are Elizabeth M. Davenport, Ph.D., Laura A. Flashman, Ph.D., Jillian Urban, Ph.D., Srikantam S. Nagarajan, Ph.D., Kiran Solingapuram Sai, Ph.D., Joel Stitzel, Ph.D., and Joseph A. Maldjian, M.D.
This work was supported by the National Institutes of Health (NIH) grants R01NS082453 and R01NS091602, NIH grant F32-NS119375, a Canadian Institutes of Health Research (CIHR) Banting Postdoctoral Fellowship (BPF-186555), and a CIHR Canada Research Chair (CRC-2023-00300).
Radiological Society of North America. "Concussions slow brain activity of high school football players." ScienceDaily. ScienceDaily, 27 November 2024. <www.sciencedaily.com/releases/2024/11/241127004157.htm>.
A new study of high school football players found that concussions affect an often-overlooked but important brain signal. The findings are being presented next week at the annual meeting of the Radiological Society of North America (RSNA).
Reports have emerged in recent years warning about the potential harms of youth contact sports on developing brains. Contact sports, including high school football, carry a risk of concussion. Symptoms of concussion commonly include cognitive disturbances, such as difficulty with balancing, memory or concentration.
Many concussion studies focus on periodic brain signals. These signals appear in rhythmic patterns and contribute to brain functions such as attention, movement or sensory processing. Not much is known about how concussions affect other aspects of brain function, specifically, brain signals that are not rhythmic.
"Most previous neuroscience research has focused on rhythmic brain signaling, which is also called periodic neurophysiology," said study lead author Kevin C. Yu, B.S., a neuroscience student at Wake Forest University School of Medicine in Winston-Salem, North Carolina. "On the other hand, aperiodic neurophysiology refers to brain signals that are not rhythmic."
Aperiodic activity is typically treated as 'background noise' on brain scans, but recent studies have shown that this background noise may play a key role in how the brain functions.
"While it's often overlooked, aperiodic activity is important because it reflects brain cortical excitability," said study senior author Christopher T. Whitlow, M.D., Ph.D., M.H.A., Meschan Distinguished Professor and Enterprise Chair of Radiology at Wake Forest University School of Medicine.
Cortical excitability is a vital part of brain function. It reflects how nerve cells, or neurons, in the brain's cortex respond to stimulation and plays a key role in cognitive functions like learning and memory, information processing, decision making, motor control, wakefulness and sleep.
To gain a better understanding of brain rhythms and trauma, the researchers sought to identify the impacts of concussions on aperiodic activity.
Pre- and post-season resting-state magnetoencephalography (MEG) data was collected from 91 high school football players, of whom 10 were diagnosed with a concussion. MEG is a neuroimaging technique that measures the magnetic fields that the brain's electrical currents produce.
A clinical evaluation tool for concussions called the Post-Concussive Symptom Inventory was correlated with pre- and post-season physical, cognitive and behavioral symptoms.
High school football players who sustained concussions displayed slowed aperiodic activity. Aperiodic slowing was strongly associated with worse post-concussion cognitive symptoms and test scores.
Slowed aperiodic activity was present in areas of the brain that contain chemicals linked with concussion symptoms like impaired concentration and memory.
"This study is important because it provides insight into both the mechanisms and the clinical implications of concussion in the maturing adolescent brain," said co-lead author Alex I. Wiesman, Ph.D., assistant professor at Simon Fraser University in Burnaby, British Columbia, Canada. "Reduced excitability is conceptually a very different brain activity change than altered rhythms and means that a clear next step for this work is to see whether these changes are related to effects of concussion on the brain's chemistry."
The results highlight the importance of protective measures in contact sports. The researchers cautioned that young players should always take the necessary time to fully recover from a concussion before returning to any sport.
The findings from the study may also influence tracking of post-concussion symptoms and aid in finding new treatments to improve recovery.
"Our study opens the door to new ways of understanding and diagnosing concussions, using this novel type of brain activity that is associated with concussion symptoms," Dr. Whitlow said. "It highlights the importance of monitoring kids carefully after any head injury and taking concussions seriously."
Other co-authors are Elizabeth M. Davenport, Ph.D., Laura A. Flashman, Ph.D., Jillian Urban, Ph.D., Srikantam S. Nagarajan, Ph.D., Kiran Solingapuram Sai, Ph.D., Joel Stitzel, Ph.D., and Joseph A. Maldjian, M.D.
This work was supported by the National Institutes of Health (NIH) grants R01NS082453 and R01NS091602, NIH grant F32-NS119375, a Canadian Institutes of Health Research (CIHR) Banting Postdoctoral Fellowship (BPF-186555), and a CIHR Canada Research Chair (CRC-2023-00300).
Radiological Society of North America. "Concussions slow brain activity of high school football players." ScienceDaily. ScienceDaily, 27 November 2024. <www.sciencedaily.com/releases/2024/11/241127004157.htm>.
Monday, November 25, 2024
Unattended children redux
It was dinnertime on October 30, 2024, when police handcuffed Brittany Patterson in front of three of her four children and drove her to the station in Fannin County, Georgia. She was then fingerprinted, photographed, and dressed in an orange jumpsuit.
Hours earlier, around noon, Patterson had driven her eldest son to a medical appointment. Her youngest son, 11-year-old Soren, intended to come along but wasn't around when it was time to leave.
"I figured he was in the woods, or at grandma's house," says Patterson, who lives on 16 acres with her kids and her father. (Her husband works out of state). There is no shortage of family in the vicinity. Patterson's mother and sisters live just two minutes away.
Soren, however, was not playing in the woods. He had decided to walk to downtown Mineral Bluff, a town of just 370 people. It's not quite a mile from his house. A woman who saw him walking alongside the road—speed limit: 25 in some places, 35 in others—asked him if he was OK. He said yes.
Nevertheless, she called the police.
A female sheriff picked up the boy and called Patterson. "She asked me if I knew he was downtown and I said no," says Patterson.
Patterson was upset that Soren had gone to town without letting anyone know, but says there was hardly reason to worry.
"I was not panicking as I know the roads and know he is mature enough to walk there without incident," she says.
The sheriff disagreed.
"She kept mentioning how he could have been run over, or kidnapped or 'anything' could have happened," recalls Patterson.
The sheriff drove Soren home and left him with his grandfather. After returning to the house, Patterson scolded her son—and that, she thought, was that.
But at 6:30 p.m. that night, the sheriff returned with another officer. They told Patterson to turn around and put her hands behind her back. As three of her kids watched, Patterson was handcuffed. The sheriff took her purse and phone, put her in the cruiser, and hauled her off to jail.
To Patterson, none of this made sense. She had grown up in the area with plenty of unsupervised time to wander and play and was raising her kids that way, too.
"The mentality here is more Free-Range," she says.
Patterson was soon released on a $500 bail. The next day, a case manager from the Division of Family and Children Services (DFCS) came out for a home visit, and even went to interview Patterson's oldest son at his school. The case manager told Patterson that everything seemed fine, but declined to comment to Reason.
A few days later, DFCS presented Patterson with a "safety plan" for her to sign. It would require her to delegate a "safety person" to be a "knowing participant and guardian" and watch over the children whenever she leaves home. The plan would also require Patterson to download an app onto her son's phone allowing for his location to be monitored. (The day when it will be illegal not to track one's kids is rapidly approaching.)
Patterson did not want to be compelled to track her son. Recalling a similar case, she contacted attorney David DeLugas. DeLugas is the head of ParentsUSA, a nonprofit that often provides pro bono legal help to parents wrongly arrested and prosecuted for child neglect. A GoFundMe has been established to help ParentsUSA cover the Pattersons' legal expenses.
As Patterson's counsel, DeLugas called the assistant district attorney (ADA) to discuss the case. He recorded the conversation, which is legal in Georgia. The ADA told DeLugas that if Patterson would sign the safety plan, the criminal charges would be dropped.
DeLugas responded that if Patterson had to sign a safety plan simply because her son walked someplace without her knowing his exact location, it would stop him from visiting friends or having any independence whatsoever. But the ADA maintained that Soren had been in danger, and thus a safety plan was necessary.
The matter was left unsettled.
With safety plans, the veiled threat is that if you don't sign, your children could be taken away, says DeLugas. In this case, he says, the unspoken deal seems to be: Sign it and the state won't prosecute. If the state does prosecute, Patterson could face a reckless conduct charge, a $1,000 fine, and a year in jail.
DeLugas would like to see Georgia pass a law that permits the authorities to check up on kids and then leave them be as long as they aren't hurt, in distress, or in actual, immediate danger from an identifiable source. Meanwhile, as if this case could not get weirder, DCFS just mailed Soren a birthday card signed by the case manager. Soren turned 11 over the weekend.
Birthday greetings do not change the facts. Patterson knows that refusing to sign the safety plan could get her in trouble. But she is resolute.
"I will not sign," she says.
https://reason.com/2024/11/11/mom-jailed-for-letting-10-year-old-walk-alone-to-town/
Hours earlier, around noon, Patterson had driven her eldest son to a medical appointment. Her youngest son, 11-year-old Soren, intended to come along but wasn't around when it was time to leave.
"I figured he was in the woods, or at grandma's house," says Patterson, who lives on 16 acres with her kids and her father. (Her husband works out of state). There is no shortage of family in the vicinity. Patterson's mother and sisters live just two minutes away.
Soren, however, was not playing in the woods. He had decided to walk to downtown Mineral Bluff, a town of just 370 people. It's not quite a mile from his house. A woman who saw him walking alongside the road—speed limit: 25 in some places, 35 in others—asked him if he was OK. He said yes.
Nevertheless, she called the police.
A female sheriff picked up the boy and called Patterson. "She asked me if I knew he was downtown and I said no," says Patterson.
Patterson was upset that Soren had gone to town without letting anyone know, but says there was hardly reason to worry.
"I was not panicking as I know the roads and know he is mature enough to walk there without incident," she says.
The sheriff disagreed.
"She kept mentioning how he could have been run over, or kidnapped or 'anything' could have happened," recalls Patterson.
The sheriff drove Soren home and left him with his grandfather. After returning to the house, Patterson scolded her son—and that, she thought, was that.
But at 6:30 p.m. that night, the sheriff returned with another officer. They told Patterson to turn around and put her hands behind her back. As three of her kids watched, Patterson was handcuffed. The sheriff took her purse and phone, put her in the cruiser, and hauled her off to jail.
To Patterson, none of this made sense. She had grown up in the area with plenty of unsupervised time to wander and play and was raising her kids that way, too.
"The mentality here is more Free-Range," she says.
Patterson was soon released on a $500 bail. The next day, a case manager from the Division of Family and Children Services (DFCS) came out for a home visit, and even went to interview Patterson's oldest son at his school. The case manager told Patterson that everything seemed fine, but declined to comment to Reason.
A few days later, DFCS presented Patterson with a "safety plan" for her to sign. It would require her to delegate a "safety person" to be a "knowing participant and guardian" and watch over the children whenever she leaves home. The plan would also require Patterson to download an app onto her son's phone allowing for his location to be monitored. (The day when it will be illegal not to track one's kids is rapidly approaching.)
Patterson did not want to be compelled to track her son. Recalling a similar case, she contacted attorney David DeLugas. DeLugas is the head of ParentsUSA, a nonprofit that often provides pro bono legal help to parents wrongly arrested and prosecuted for child neglect. A GoFundMe has been established to help ParentsUSA cover the Pattersons' legal expenses.
As Patterson's counsel, DeLugas called the assistant district attorney (ADA) to discuss the case. He recorded the conversation, which is legal in Georgia. The ADA told DeLugas that if Patterson would sign the safety plan, the criminal charges would be dropped.
DeLugas responded that if Patterson had to sign a safety plan simply because her son walked someplace without her knowing his exact location, it would stop him from visiting friends or having any independence whatsoever. But the ADA maintained that Soren had been in danger, and thus a safety plan was necessary.
The matter was left unsettled.
With safety plans, the veiled threat is that if you don't sign, your children could be taken away, says DeLugas. In this case, he says, the unspoken deal seems to be: Sign it and the state won't prosecute. If the state does prosecute, Patterson could face a reckless conduct charge, a $1,000 fine, and a year in jail.
DeLugas would like to see Georgia pass a law that permits the authorities to check up on kids and then leave them be as long as they aren't hurt, in distress, or in actual, immediate danger from an identifiable source. Meanwhile, as if this case could not get weirder, DCFS just mailed Soren a birthday card signed by the case manager. Soren turned 11 over the weekend.
Birthday greetings do not change the facts. Patterson knows that refusing to sign the safety plan could get her in trouble. But she is resolute.
"I will not sign," she says.
https://reason.com/2024/11/11/mom-jailed-for-letting-10-year-old-walk-alone-to-town/
See: https://childnervoussystem.blogspot.com/2015/04/unattended-children.html
Thursday, November 21, 2024
Eladocagene exuparvovec for aromatic L-amino acid decarboxylase (AADC) deficiency
Kebilidi (eladocagene exuparvovec-tneq; PTC Therapeutics, Warren, NJ) has been granted Food and Drug Administration (FDA) approval under the Accelerated Approval pathway for the treatment of adult and pediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency. Kebilidi is an adeno-associated virus vector-based gene therapy administered by intraputaminal infusion. It is the first gene therapy to receive FDA approval for the treatment of this genetic disorder.
The FDA’s decision was based on findings from an ongoing global clinical trial demonstrating safety and efficacy of Kebilidi as a treatment for AADC deficiency. The open-label, single-arm clinical study includes 13 pediatric participants with confirmed diagnosis of AADC deficiency with no gross motor function and decreased AADC activity in plasma. No gross motor function comprises the most severe presentation of AADC deficiency. All participants received treatment with Kebilidi with outcomes compared with a natural history cohort.12 of the 13 participants completed motor milestone assessments at week 48 after receiving treatment.
8 of 12 treated participants showed gross motor function improvement, which has not been reported in untreated patients, demonstrating the efficacy of Kebilidi treatment.
The most common adverse reactions are dyskinesia, fever, low blood pressure, anemia, increased saliva production, insomnia, procedural complications (eg, respiratory and cardiac arrest), and low levels of potassium, phosphate, and/or magnesium.
Confirmatory evidence will be provided after long-term follow-up of study participants.
"I am proud of our team's unwavering commitment to achieve this important regulatory milestone,” said Matthew B. Klein, MD, CEO of PTC Therapeutics. “We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."
AADC deficiency is a rare genetic disorder associated with mutations in the DDC gene that encodes the aromatic L-amino acid decarboxylase enzyme. People present symptoms within the first few months of life, including hypotonia, developmental delay, dystonia and dyskinesia, gastrointestinal dysmotility, autonomic symptoms, and oculogyric crises. Children with this disorder are at high risk of death within the first 10 years of life.
The FDA authorized the use of the SmartFlow Neuro Cannula (Clearpoint Neuro, Solana Beach, CA) for use in administering Kebilidi.
https://practicalneurology.com/news/fda-grants-accelerated-approval-to-gene-therapy-for-the-treatment-of-aadc-deficiency
Kanjia MK, Jooste EH, Illig M, Neifeld Capps J, Eisner C, Fan SZ, Lenarczyk J, Wojdacz R. Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency. Paediatr Anaesth. 2024 Oct 22. doi: 10.1111/pan.15025. Epub ahead of print. PMID: 39435566.
Abstract
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.
Lee HM, Mercimek-Andrews S, Horvath G, Marchese D, Poulin RE 3rd, Krolick A, Tierney KL, Turna J, Wei J, Hwu WL. A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients. Orphanet J Rare Dis. 2024 Jan 18;19(1):17. doi: 10.1186/s13023-024-03019-x. PMID: 38238766; PMCID: PMC10797739.
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.
Simons CL, Hwu WL, Zhang R, Simons MJHG, Bergkvist M, Bennison C. Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study. Adv Ther. 2023 Dec;40(12):5399-5414. doi: 10.1007/s12325-023-02689-6. Epub 2023 Oct 6. PMID: 37803205; PMCID: PMC10611606.
Abstract
Introduction: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disease with symptoms including movement disorders, developmental delays, and autonomic symptoms starting from birth; further, patients with AADC deficiency are at a high risk of death in the first decade of life. Limited information on the impact of treatment with gene therapy on patients' disease trajectories and survival, quality-of-life, and resource usage benefits are available.
Method: A cohort-based model with a lifetime horizon has been developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a UK setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management.
Results: The model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results.
Conclusion: This study assessed long-term outcomes for patients with AADC deficiency. Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.
The FDA’s decision was based on findings from an ongoing global clinical trial demonstrating safety and efficacy of Kebilidi as a treatment for AADC deficiency. The open-label, single-arm clinical study includes 13 pediatric participants with confirmed diagnosis of AADC deficiency with no gross motor function and decreased AADC activity in plasma. No gross motor function comprises the most severe presentation of AADC deficiency. All participants received treatment with Kebilidi with outcomes compared with a natural history cohort.12 of the 13 participants completed motor milestone assessments at week 48 after receiving treatment.
8 of 12 treated participants showed gross motor function improvement, which has not been reported in untreated patients, demonstrating the efficacy of Kebilidi treatment.
The most common adverse reactions are dyskinesia, fever, low blood pressure, anemia, increased saliva production, insomnia, procedural complications (eg, respiratory and cardiac arrest), and low levels of potassium, phosphate, and/or magnesium.
Confirmatory evidence will be provided after long-term follow-up of study participants.
"I am proud of our team's unwavering commitment to achieve this important regulatory milestone,” said Matthew B. Klein, MD, CEO of PTC Therapeutics. “We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."
AADC deficiency is a rare genetic disorder associated with mutations in the DDC gene that encodes the aromatic L-amino acid decarboxylase enzyme. People present symptoms within the first few months of life, including hypotonia, developmental delay, dystonia and dyskinesia, gastrointestinal dysmotility, autonomic symptoms, and oculogyric crises. Children with this disorder are at high risk of death within the first 10 years of life.
The FDA authorized the use of the SmartFlow Neuro Cannula (Clearpoint Neuro, Solana Beach, CA) for use in administering Kebilidi.
https://practicalneurology.com/news/fda-grants-accelerated-approval-to-gene-therapy-for-the-treatment-of-aadc-deficiency
Kanjia MK, Jooste EH, Illig M, Neifeld Capps J, Eisner C, Fan SZ, Lenarczyk J, Wojdacz R. Optimizing the anesthetic care of patients with aromatic l-amino acid decarboxylase deficiency. Paediatr Anaesth. 2024 Oct 22. doi: 10.1111/pan.15025. Epub ahead of print. PMID: 39435566.
Abstract
Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder that results in a lack of the monoamine neurotransmitters dopamine, serotonin, norepinephrine, and epinephrine. Patients present with a wide spectrum of symptoms, including motor and autonomic dysfunction, hypotonia, and developmental delay, often before the age of one. Until recently, treatment options were limited to symptom control, but the recent approval of the first gene therapy for AADC deficiency in Europe and the UK has provided an alternative to treating symptoms for this disease. Eladocagene exuparvovec is a one-time gene therapy, administered bilaterally to the putamen by magnetic resonance imaging-guided stereotactic neurosurgery. While administration of the gene therapy itself is minimally invasive, the anesthetic management of patients with AADC deficiency is challenging due to the absence of sympathetic regulation secondary to the lack of adrenergic neurotransmitters. Optimal anesthetic management requires an understanding of the complex and heterogeneous nature of the disease. Hemodynamic instability, temperature dysregulation, and hypoglycemia are of primary concern, but there are also challenges regarding intravenous access and airway management. A thorough preoperative assessment is essential and should be guided by the patient's history. Advanced planning is necessary regarding the timing of the procedure schedule and operative plan; meticulous preparation, simulation for the operating room, as well as communication with all perioperative staff members, are crucial. Intraoperatively, utmost care must be taken to protect the skin, maintain body temperature, and to prepare for inotropic and/or glycemic support as needed. Postoperative intensive care management is necessary for consideration of postoperative extubation and provision of supportive care. With careful planning, preparation, and vigilance, patients with AADC deficiency can safely undergo anesthesia.
Lee HM, Mercimek-Andrews S, Horvath G, Marchese D, Poulin RE 3rd, Krolick A, Tierney KL, Turna J, Wei J, Hwu WL. A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients. Orphanet J Rare Dis. 2024 Jan 18;19(1):17. doi: 10.1186/s13023-024-03019-x. PMID: 38238766; PMCID: PMC10797739.
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.
Simons CL, Hwu WL, Zhang R, Simons MJHG, Bergkvist M, Bennison C. Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study. Adv Ther. 2023 Dec;40(12):5399-5414. doi: 10.1007/s12325-023-02689-6. Epub 2023 Oct 6. PMID: 37803205; PMCID: PMC10611606.
Abstract
Introduction: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disease with symptoms including movement disorders, developmental delays, and autonomic symptoms starting from birth; further, patients with AADC deficiency are at a high risk of death in the first decade of life. Limited information on the impact of treatment with gene therapy on patients' disease trajectories and survival, quality-of-life, and resource usage benefits are available.
Method: A cohort-based model with a lifetime horizon has been developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a UK setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management.
Results: The model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results.
Conclusion: This study assessed long-term outcomes for patients with AADC deficiency. Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.
Monday, November 18, 2024
Biochemical determinants for diagnosis and prediction of severity in 5q spinal muscular atrophy
Saffari A, Niesert M, Cannet C, Blaschek A, Hahn A, Johannsen J, Kockaya M, Kölbel H, Hoffmann GF, Claus P, et al. Identification of Biochemical Determinants for Diagnosis and Prediction of Severity in 5q Spinal Muscular Atrophy Using 1H-Nuclear Magnetic Resonance Metabolic Profiling in Patient-Derived Biofluids. International Journal of Molecular Sciences. 2024; 25(22):12123. https://doi.org/10.3390/ijms252212123
Abstract
This study explores the potential of 1H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-naïve patients with SMA across five German centers were analyzed using 1H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84–91%) and specificity (91–94%) in distinguishing treatment-naïve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that 1H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.
Abstract
This study explores the potential of 1H-NMR spectroscopy-based metabolic profiling in various biofluids as a diagnostic and predictive modality to assess disease severity in individuals with 5q spinal muscular atrophy. A total of 213 biosamples (urine, plasma, and CSF) from 153 treatment-naïve patients with SMA across five German centers were analyzed using 1H-NMR spectroscopy. Prediction models were developed using machine learning algorithms which enabled the patients with SMA to be grouped according to disease severity. A quantitative enrichment analysis was employed to identify metabolic pathways associated with disease progression. The results demonstrate high sensitivity (84–91%) and specificity (91–94%) in distinguishing treatment-naïve patients with SMA from controls across all biofluids. The urinary and plasma profiles differentiated between early-onset (type I) and later-onset (type II/III) SMA with over 80% accuracy. Key metabolic differences involved alterations in energy and amino acid metabolism. This study suggests that 1H-NMR spectroscopy based metabolic profiling may be a promising, non-invasive tool to identify patients with SMA and for severity stratification, potentially complementing current diagnostic and prognostic strategies in SMA management.
Saturday, November 16, 2024
Transparency update 5
When CNN aired a scathing report in 2015, claiming the death rate at St. Mary’s Medical Center’s pediatric cardiac surgery center was three times higher than the national average, the hospital blasted the cable news giant, calling its reporting sensational and its numbers inaccurate.
Then, over the next several years, it quietly paid $102.4 million to settle nine lawsuits filed against it by the grieving parents of children who died or were permanently disabled after being treated at the now-shuttered kid’s surgery unit.
While the settlement amounts aren’t included in the files of the nine medical malpractice cases in Palm Beach County Circuit Court, they were obtained by lawyers who successfully defended CNN in a defamation lawsuit filed against it by Dr. Michael Black, director of the troubled unit.
CNN lawyers Martin Reeder and Charles Tobin used the massive payouts to bolster their claims that not only was the CNN report accurate, but that St. Mary’s agreed to write multimillion-dollar checks rather than fight the allegations of botched surgeries.
Dallas-based Tenet Healthcare, which owns the hospital on 45th Street in West Palm Beach, didn’t return emails for comment about why it settled the cases or why some of them weren’t recorded on the website of the Florida Office of Insurance Regulation as required by state law.
The largest settlement of $38.2 million was for the ongoing care of an Okeechobee County girl, who was left partially paralyzed at 6 weeks old when a clamp, left on twice as long as recommended, cut blood flow to her spine when she was undergoing heart surgery, court records show.
There was a $12 million settlement to the parents of a 16-day-old infant who languished for hours before dying after a 10-hour surgery to repair her heart. The same amount was paid to the parents of a now 9-year-old Palm Beach County girl who has required around-the-clock care for developmental disabilities and other infirmities she suffered since undergoing heart surgery when she was 18 days old.
The other settlements ranged from $3.5 million to $8.9 million.
Misgivings about the program intensified after a team of independent pediatric heart surgeons reviewed its operation and warned it didn’t have the expertise to perform surgery on infants under 6 months old or those with complex heart conditions.
Later, it was revealed that Black wasn’t a U.S. board-certified cardiovascular surgeon, a requirement under state law for hospitals operating such specialized and high-risk programs. Black's attorneys countered that he was certified by Canadian equivalents of the American board and state officials had signed off on it.
St. Mary’s closed the unit in August 2015, two months after CNN detailed the ignored warnings and the deaths of six of the unit’s 48 young patients from 2011 until 2013. It pointed out that the program’s 12.5% death rate was three times higher than the national average of 3.3% as reported by The Society of Thoracic Surgeons. Before the unit was folded, another three children died.
Even after the unit was dismantled, St. Mary’s continued to keep Black on the payroll, CNN lawyers said in court documents. While Black no longer performed surgeries, he continued to collect his $800,000 annual salary until August 2018, they said.
And, the costs continue to mount.
Black’s defamation suit, initially filed against CNN and reporter Elizabeth Cohen, producer John Bonifield, digital editor Dana Ford and host Anderson Cooper, was thrown out in November. Black has appealed.
He is also asking the Florida Supreme Court to overturn a previous decision that barred him from seeking punitive damages against CNN.
All of his legal fees are being paid by Tenet, Reeder and Tobin said in court documents.
Last week, Black’s attorneys were back in Palm Beach County Circuit Court, trying to persuade Senior Judge Richard Oftedal not to force Black to pay $320,000 in court costs CNN incurred in an appeal.
While the amount pales compared to the money Tenet has already shelled out, Virginia lawyer Joseph Oliveri argued vigorously, calling the costs “wildly excessive” and premature. Oftedal should delay a decision until Black’s appeals run out, he wrote.
Oftedal showed no interest in waiting, but agreed to hold another hearing in April so attorneys can flesh out their arguments.
Like the 4th District Court of Appeal, which threw out Black’s request to seek punitive damages against CNN, Oftedal ruled Nov. 27 that there was nothing defamatory about CNN’s report.
Black unsuccessfully argued that the news outlet should have used mortality numbers adjusted for risk. Oftedal called the claim “disingenuous,” pointing out that St. Mary’s and Tenet repeatedly refused CNN’s requests for the adjusted numbers.
“We believe that we have provided you sufficient information about our program and trust that you can complete your story with the information we have already provided,” a hospital spokesperson wrote CNN reporters in April 2015, again rejecting their request for adjusted numbers and cutting off further communication.
Aside from St. Mary’s stone-walling, Oftedal said there is disagreement among medical experts about which numbers — the raw numbers or those that are risk-adjusted — are more meaningful. Further, CNN quoted then-hospital CEO Davide Carbone criticizing its use of raw numbers. “(It) could potentially lead to providing misleading information to consumers,” he said.
In any case, Oftedal ruled, Black had not been defamed.
“The overall picture painted by CNN for its viewers and readers depicted a program in crisis, besieged by parents and critics alike, all of whom expressed serious concerns regarding the competency and qualifications of Dr. Black and for a program that ignored repeated warnings and alarm bells calling for a cessation of these highly complex pediatric open heart surgeries,” he wrote.
His conclusion: “Because CNN’s reporting as a whole was substantially true, Dr. Black has not raised a triable issue of material falsity.”
Then, over the next several years, it quietly paid $102.4 million to settle nine lawsuits filed against it by the grieving parents of children who died or were permanently disabled after being treated at the now-shuttered kid’s surgery unit.
While the settlement amounts aren’t included in the files of the nine medical malpractice cases in Palm Beach County Circuit Court, they were obtained by lawyers who successfully defended CNN in a defamation lawsuit filed against it by Dr. Michael Black, director of the troubled unit.
CNN lawyers Martin Reeder and Charles Tobin used the massive payouts to bolster their claims that not only was the CNN report accurate, but that St. Mary’s agreed to write multimillion-dollar checks rather than fight the allegations of botched surgeries.
Dallas-based Tenet Healthcare, which owns the hospital on 45th Street in West Palm Beach, didn’t return emails for comment about why it settled the cases or why some of them weren’t recorded on the website of the Florida Office of Insurance Regulation as required by state law.
The largest settlement of $38.2 million was for the ongoing care of an Okeechobee County girl, who was left partially paralyzed at 6 weeks old when a clamp, left on twice as long as recommended, cut blood flow to her spine when she was undergoing heart surgery, court records show.
There was a $12 million settlement to the parents of a 16-day-old infant who languished for hours before dying after a 10-hour surgery to repair her heart. The same amount was paid to the parents of a now 9-year-old Palm Beach County girl who has required around-the-clock care for developmental disabilities and other infirmities she suffered since undergoing heart surgery when she was 18 days old.
The other settlements ranged from $3.5 million to $8.9 million.
Misgivings about the program intensified after a team of independent pediatric heart surgeons reviewed its operation and warned it didn’t have the expertise to perform surgery on infants under 6 months old or those with complex heart conditions.
Later, it was revealed that Black wasn’t a U.S. board-certified cardiovascular surgeon, a requirement under state law for hospitals operating such specialized and high-risk programs. Black's attorneys countered that he was certified by Canadian equivalents of the American board and state officials had signed off on it.
St. Mary’s closed the unit in August 2015, two months after CNN detailed the ignored warnings and the deaths of six of the unit’s 48 young patients from 2011 until 2013. It pointed out that the program’s 12.5% death rate was three times higher than the national average of 3.3% as reported by The Society of Thoracic Surgeons. Before the unit was folded, another three children died.
Even after the unit was dismantled, St. Mary’s continued to keep Black on the payroll, CNN lawyers said in court documents. While Black no longer performed surgeries, he continued to collect his $800,000 annual salary until August 2018, they said.
And, the costs continue to mount.
Black’s defamation suit, initially filed against CNN and reporter Elizabeth Cohen, producer John Bonifield, digital editor Dana Ford and host Anderson Cooper, was thrown out in November. Black has appealed.
He is also asking the Florida Supreme Court to overturn a previous decision that barred him from seeking punitive damages against CNN.
All of his legal fees are being paid by Tenet, Reeder and Tobin said in court documents.
Last week, Black’s attorneys were back in Palm Beach County Circuit Court, trying to persuade Senior Judge Richard Oftedal not to force Black to pay $320,000 in court costs CNN incurred in an appeal.
While the amount pales compared to the money Tenet has already shelled out, Virginia lawyer Joseph Oliveri argued vigorously, calling the costs “wildly excessive” and premature. Oftedal should delay a decision until Black’s appeals run out, he wrote.
Oftedal showed no interest in waiting, but agreed to hold another hearing in April so attorneys can flesh out their arguments.
Like the 4th District Court of Appeal, which threw out Black’s request to seek punitive damages against CNN, Oftedal ruled Nov. 27 that there was nothing defamatory about CNN’s report.
Black unsuccessfully argued that the news outlet should have used mortality numbers adjusted for risk. Oftedal called the claim “disingenuous,” pointing out that St. Mary’s and Tenet repeatedly refused CNN’s requests for the adjusted numbers.
“We believe that we have provided you sufficient information about our program and trust that you can complete your story with the information we have already provided,” a hospital spokesperson wrote CNN reporters in April 2015, again rejecting their request for adjusted numbers and cutting off further communication.
Aside from St. Mary’s stone-walling, Oftedal said there is disagreement among medical experts about which numbers — the raw numbers or those that are risk-adjusted — are more meaningful. Further, CNN quoted then-hospital CEO Davide Carbone criticizing its use of raw numbers. “(It) could potentially lead to providing misleading information to consumers,” he said.
In any case, Oftedal ruled, Black had not been defamed.
“The overall picture painted by CNN for its viewers and readers depicted a program in crisis, besieged by parents and critics alike, all of whom expressed serious concerns regarding the competency and qualifications of Dr. Black and for a program that ignored repeated warnings and alarm bells calling for a cessation of these highly complex pediatric open heart surgeries,” he wrote.
His conclusion: “Because CNN’s reporting as a whole was substantially true, Dr. Black has not raised a triable issue of material falsity.”
https://www.wlrn.org/health/2024-03-29/st-marys-medical-center-pediatric-cardiac-settlements-top-100-million
Dealing with "defectives"
Courtesy of a colleague
No abstract. From the article:
Kennedy and Lennox on eugenics. The 1930s and 1940s were an especially turbulent period of history for the United States and the world, marked as it was by the Great Depression and World War II. First in 1936 and 1938, then on different occasions over subsequent years, Kennedy and Lennox each made known their own thinking about how “defective” individuals should be dealt with. Summarized here are some of these two neurologists’ most relevant and informative utterances on this subject, in which their arguments, supporting evidence, recommendations, and personal values are stated or implied.
Euthanasia. Lennox (WL) in an article (“Should They Live? Certain Economic Aspects of Medicine” ) published by the Phi Beta Kappa honor society’s journal American Scholar (AS) in 1938, and Kennedy (FK) first in an article (“Euthanasia: To Be or Not To Be” ) published by the popular weekly magazine Colliers in 1939 and then in a presentation (“The Problem of Social Control of the Congenital Defective: Education, Sterilization, Euthanasia”) made at a May 1941 American Psychiatric Association (APA) luncheon, both called for killing “defectives.”
WL: . . . the congenital idiots or monsters... What shall be done with these?... (Society) should eliminate . . . the idiots and monsters . . . The selection of the congenitally and hopelessly mindless for elimination would offer no more difficulties than their selection for lifelong incarceration. A court-appointed medical committee would be sufficient.(see Lennox reference below)
FK: What to do with the hopelessly unfit? . . . the place for euthanasia, I believe, is for the completely hopeless defective: nature’s mistake; something we hustle out of sight, which should never have been seen at all. These should be relieved of the burden of living . . . to allow them to continue such a living is sheer sentimentality, and cruel too; we deny them as much solace as we give our stricken horse. Here we may most kindly kill.(see Kennedy reference below)
The American Journal of Psychiatry (AJP) published Kennedy’s remarks in its July 1942 issue along with a lengthy, passionate rebuttal by the child psychiatrist Leo Kanner of Johns Hopkins. Kanner, who is credited with the classic description of infantile autism, challenged Kennedy’s view of the “feebleminded,” pleading in effect for a more sympathetic one. (see Kanner reference below) In the same issue, an editorial only a little shorter than Kennedy’s contribution summarized and assessed the two doctors’ respective arguments: (see Euthanasia citation below)
. . . the differences narrow down to a single point: for a specified group of defectives and under specified conditions Dr. Kennedy advocates euthanasia; Dr. Kanner opposes this procedure. Both writers are agreed as to the existence of the group in question and the hopelessness of their condition; one proposes a method of disposal which he believes would bring relief to all concerned, the other prefers to let the situation remain as it is... (Kennedy) offers strong arguments in support of his position. Dr. Kanner opposes this position but in his paper presents no arguments beyond the statement: “An idiotic child may have fond parents who want him alive.”
Euthanasia: “voluntary” versus “involuntary.” Although both wanted to legalize euthanasia for the “defectives” who could not give consent, Kennedy and Lennox differed on legalizing it for those seeking assistance in ending their own lives. Lennox was in favor, whereas Kennedy was outspoken in opposition on practical and philosophical grounds.
FK: . . . I have many instances in my own experience of seemingly fatally ill persons who for years after, lived useful lives... (B)esides, a civilization that deliberately shuts itself off from the bearing of pain and the presence of struggle and finally makes its bid for the softer life or death, is already slipping down the ways. To do this is a sign of degradation and defeat.3
Having been appointed the Euthanasia Society of America’s (ESA) founder as president only a month earlier, and with “a mercy death law” then under consideration by the New York state legislature, Kennedy appeared in the company of two others from the ESA on a program to “present the case for euthanasia—referred to in the official program as ‘the granting of peaceful death to incurable sufferers.’ ” As reported on February 14, 1939, this took place before “an overflow meeting of the Society of Medical Jurisprudence,” the NYT headlining the story, “Dr. Kennedy Gives Views: Euthanasia Needed Mainly For Defectives, Not For Easing Pain, He Declares.”
. . . the physician who was a “gentleman” was equipped to assist in a “necessary journey to death” . . . Then he turned to the “absurd and misplaced sentimental kindness” that seeks to preserve the life of a “person who is not a person.” ... “If the law sought to restrict euthanasia to those who could speak out for it, and thus overlooked those creatures who cannot speak,” Dr. Kennedy declared, “then, I say as Dickens did, ‘The law’s an ass.’ It’s time the law changed its mind.”
A few days later, Bernard Sachs, a past president of the ANA, responded to his “good friend” Kennedy in a letter to the NYT, summing up, “Irrespective of religious doctrines or sanctions, it is the solemn duty of the physician to prolong life, not to end it.” After another few days, the NYT printed a letter from the Cornell professor restating his support for euthanasia “for creatures born defective” and opposition to it “for those persons who, having been well, are ill,” and making clear these opinions were “entirely personal,” not “to be construed as the policy of the Euthanasia Society of America.” The next week, only a month after assuming the position, Kennedy resigned the ESA presidency.
Euthanasia: “active” versus “passive.” Like Malthus more than a century before, Lennox advocated a “non-interventional” approach to lifethreatening infectious illnesses for overpopulated countries to reduce their overall numbers. He also called for the same “non-interventional” approach, or what has been labeled “passive” euthanasia, for “defective” individuals overcrowding asylums and placing an economic burden on society. WL:
. . . until wealth could be increased or birthrates reduced, medicine in the Orient should abandon attempts to wholesale prevention of infection... There is not the same disproportion between population and material resources in America as in the Orient but if we are far-sighted we shall begin to do something about that portion of our population which is a heavy and permanent liability... Should the lives of incurables in institutions be prolonged by prophylactic injections against typhoid fever, scarlet fever and diphtheria? The death-rate in institutions from communicable diseases is decreasing and consequently the need for more institutions is increasing. To these facts medical superintendents point with pride and taxpayers with anxiety....
Labels. Kennedy and Lennox referred to those they recommended for euthanasia variously as “idiots,” “imbeciles,” and “morons,” terms that, although offensive in modern usage, were accepted scientific labels at the time. In making their cases, Kennedy and Lennox did not limit themselves to the standard medical lexicon when speaking of “defectives” though. Kennedy, for example, labeled them “Nature’s mistakes.” Lennox reached further for images to characterize them. This former medical missionary, who went to medical school after he was turned down for theology school, saw them not as products of “Nature” but rather as the Creator’s mistakes (“the result of some slip of the hand of Him who made them, lumps of matter in human form but without human mind”). In Lennox’s view, they were, or may as well have been, inanimate, “clock case(s) without works,” which, of course, “can never tell time.” If animate, they might have “human form,” but they reminded Lennox more of the cattle he had tended as a ranch hand in his youth.
WL: As an inexperienced “hand” on a huge southwestern cattle range it used to be my job at round-up time to work on “the drag,” keeping the worn-out cows and little dogies from falling behind the herd, while the experienced cowboys rode at the head, skillfully “pointing” the wild-footed steers toward their destination. Physicians, as a class, work only on the drag— trying to keep the physically and mentally unfit in the procession...
Kennedy and Lennox saw Medicine as a player on the larger world stage, further subordinating the individual’s interests to what they perceived as the greater good. Lennox, for example, expounded on Medicine’s geopolitical possibilities, unselfconsciously suggesting not only that “birth-planning” might operate to avoid international conflict, especially between East and West, but also that “this principle of limiting certain races through limitation of offspring might be applied intranationally as well as internationally.” After opining in the fall of 1938 that “Germany in time might have solved her Jewish problems in this way,” he went on to hint that targeting of groups within the overall population might be desirable in the United States because a “solvent society must say how many and what sort are to be born”.
The views expressed by Drs. Kennedy and Lennox on eugenics were not novel nor truly exceptional among their peers and contemporaries generally. After Galton’s coinage of the term eugenics in 1883, many people of note involved themselves as active proponents of this developing “science,” if it can fairly be called such, and the movement it spawned. When Kennedy and Lennox took up the cause, though, both it and they were in their sixth decade. In the United States, enthusiasm for eugenics was by then cresting and would decline further as details of what transpired in Europe under the Nazis emerged.
Lennox WG. Should they live? Certain economic aspects of medicine. Am Scholar 1938;7:454–466, 509.
Kennedy F. The problem of social control of the congenital defective: education, sterilization, euthanasia. Am J Psychiatry 1942;99:13–16
Kanner L. Exoneration of the feebleminded. Am J Psychiatry 1942;99: 17–22.
Euthanasia. Am J Psychiatry 1942,99:141–143.
Monday, November 11, 2024
Tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations
Northrup, HopeAnnear, Nicholas M.P. et al.Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatric Neurology, Volume 123, 50 - 66.
Abstract
Background
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
Methods
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.
Results
Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
Conclusions
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Abstract
Background
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
Methods
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.
Results
Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
Conclusions
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
CHD2-related epilepsy with eyelid myoclonia
Padilla H, Pinto E Vairo F, Wirrell EC, Wong-Kisiel LC, Fine AL, Lanpher BC, Smith KM. CHD2-related epilepsy with eyelid myoclonia: Report of three cases. Epileptic Disord. 2024 Nov 6. doi: 10.1002/epd2.20305. Epub ahead of print. PMID: 39503459.
Abstract
The aim of this study is to report three cases of epilepsy with eyelid myoclonia (EEM) with CHD2 pathogenic variants. A database of 134 patients with EEM evaluated at Mayo Clinic sites was searched to identify patients with CHD2 variants. The medical records of those identified were reviewed to describe their presentation, treatment, and clinical course. Three patients (2 males, 1 female) with EEM were found to harbor de novo CHD2 pathogenic variants (c.2636C>T p.(Ala879Val), c.3734delA p. (Lys1245Asnfs*4), and c.3896delTinsCG p. (Val1299Alafs*5)). All three patients had comorbid autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit disorder (ADHD). Eyelid myoclonia was a prominent seizure type that persisted in the three patients despite trials of multiple antiseizure medications. Generalized tonic-clonic seizures occurred in two of the patients but were controlled with antiseizure medications. Genetic testing should be considered in patients presenting with EEM, especially when ADHD, ID, ASD, and drug-resistant seizures are present. Further understanding of the relationship between CHD2 variants and epileptogenesis may provide important insights into the pathogenesis of EEM.
Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Knupp KG, Nordli DR Jr, Riva A, Stern JM, Striano P, Thiele EA, Zawar I. A comprehensive narrative review of epilepsy with eyelid myoclonia. Epilepsy Res. 2023 Jul;193:107147. doi: 10.1016/j.eplepsyres.2023.107147. Epub 2023 Apr 26. PMID: 37121024.
Abstract
Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.
Abstract
The aim of this study is to report three cases of epilepsy with eyelid myoclonia (EEM) with CHD2 pathogenic variants. A database of 134 patients with EEM evaluated at Mayo Clinic sites was searched to identify patients with CHD2 variants. The medical records of those identified were reviewed to describe their presentation, treatment, and clinical course. Three patients (2 males, 1 female) with EEM were found to harbor de novo CHD2 pathogenic variants (c.2636C>T p.(Ala879Val), c.3734delA p. (Lys1245Asnfs*4), and c.3896delTinsCG p. (Val1299Alafs*5)). All three patients had comorbid autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit disorder (ADHD). Eyelid myoclonia was a prominent seizure type that persisted in the three patients despite trials of multiple antiseizure medications. Generalized tonic-clonic seizures occurred in two of the patients but were controlled with antiseizure medications. Genetic testing should be considered in patients presenting with EEM, especially when ADHD, ID, ASD, and drug-resistant seizures are present. Further understanding of the relationship between CHD2 variants and epileptogenesis may provide important insights into the pathogenesis of EEM.
Smith KM, Wirrell EC, Andrade DM, Choi H, Trenité DK, Knupp KG, Nordli DR Jr, Riva A, Stern JM, Striano P, Thiele EA, Zawar I. A comprehensive narrative review of epilepsy with eyelid myoclonia. Epilepsy Res. 2023 Jul;193:107147. doi: 10.1016/j.eplepsyres.2023.107147. Epub 2023 Apr 26. PMID: 37121024.
Abstract
Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.
Sunday, November 10, 2024
CLDN5 mutations
Deshwar AR, Cytrynbaum C, Murthy H, Zon J, Chitayat D, Volpatti J, Newbury-Ecob R, Ellard S,
Inspired by sibling patients
Allen HL, Yu EP, Noche R, Walker S, Scherer SW, Mahida S, Elitt CM, Nicolas G, Goldenberg A, Saugier-Veber P, Lecoquierre F, Dabaj I, Meddaugh H, Marble M, Keppler-Noreuil KM, Drayson L, Barañano KW, Chassevent A, Agre K, Létard P, Bilan F, Le Guyader G, Laquerrière A, Ramsey K, Henderson L, Brady L, Tarnopolsky M, Bainbridge M, Friedman J, Capri Y, Athayde L, Kok F, Gurgel-Giannetti J, Ramos LLP, Blaser S, Dowling JJ, Weksberg R. Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications. Brain. 2023 Jun 1;146(6):2285-2297. doi: 10.1093/brain/awac461. PMID: 36477332.
Abstract
The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.
Thursday, November 7, 2024
Acute toxic leukoencephalopathy
Jake Haendel had “everything going for him.” He was newly married and working as a head executive chef in Boston when he received a devastating and life-changing diagnosis.
In May 2017, Haendel noticed that his voice started to become higher pitched than normal. Initially brushing it off, it wasn’t until he started having balance issues that he decided to visit the emergency room on Memorial Day weekend.
Doctors believed he was having stroke-like symptoms, so he was admitted and given IV fluids. Haendel, now 36, had been to the hospital many times before and expected to be monitored for a few hours and then simply sent home with antibiotics. And he was right.
“They were actually about to discharge me when my wife came in and said, ‘You cannot discharge him. This is not my husband.’ She played an old voicemail for them. My voice and the voice I had been using were completely different,” he tells PEOPLE. “So the doctors and nurses and emergency room staff were like, ‘Whoa,’ and ordered an emergency MRI.”
One day later, Haendel was diagnosed with acute toxic leukoencephalopathy (ATL), a rare and often fatal brain disease caused by exposure to toxic substances. He was given six months to live.
“I woke up and there was a whole team of people in the room,” he recalls. “A doctor was sitting on the
Haendel immediately thought about his late mother, who died of breast cancer when he was 19. He remembered watching her struggle to fight the disease for 10 years before her death, a time where he struggled mentally and turned to drugs to cope.
Doctors told Haendel that in his case, the ATL was attributed to that past substance abuse. “I literally said out loud, ‘I am f—ed.’ My first thought was how disappointed my mom would be in me,” he says. “There were very powerful emotions all at once.”
“I told my wife, ‘I watched my mom die. You shouldn't have to watch me die,’” he adds.
After revealing his diagnosis, doctors pulled out a whiteboard and broke down exactly how Haendel’s disease was expected to progress. The first month he wouldn’t be able to walk, even with the help of assistive devices. Month two, he would be confined to a wheelchair until he’s unable to tolerate it due to chronic pain. By month three, he would be bedridden and lose the ability to eat, swallow and talk. In the fourth and final stage of the disease, he would slip into a coma and eventually die.
“And no one had ever survived stage four,” Haendel says.
Unfortunately, Haendel’s doctors were “right on the money with that timeframe,” and his health took a turn for the worst. “I underestimated the amount of pain I would be in,” he admits, comparing his body to a car that’s gone haywire.
By November, Haendel’s speech was fully gone. He was admitted to the neuro ICU at Massachusetts General Hospital as he continued to deteriorate. Around this time, he slipped into what doctors believed was a coma, which was consistent with the natural progression of the disease.
December 1, 2017 was the first time he heard someone refer to him as brain dead.
“One of the doctors told my wife, ‘We're really sorry Mrs. Haendel, but your husband will not make it to Christmas.’ In my head, I was bummed because I had no illusion that I was going to die. But I'm in so much pain that it was also a relief that this constant struggle was going to be over,” he explains.
“But then I heard them say I was brain dead and it's time to start considering withdrawing life support. I was contemplating, am I brain dead? How can I think, how do I have memories?” he continues. “So even though I was having those thoughts that this is going to be over soon, I was like, ‘Oh, don't do that, I'm still in here.’”
Haendel appeared to be in a vegetative state. However, unknown to his doctors, his disease triggered locked-in syndrome, a rare and serious neurological disorder where damage to the brain stem leads to complete paralysis over all voluntary muscles except for the ones that control the eyes, according to the National Organization for Rare Disorders (NORD). While he can still feel touch, pain, an itch and other sensations, and he is entirely aware of his environment and surroundings, Haendel is “locked” inside his body, as the name of the syndrome implies.
“It was the worst you can imagine,” he explains. “It was like being a prisoner in solitary confinement, but worse. You're totally paralyzed, you can't move, talk or signal. I was just talking to myself in my head. It was more of survival to keep my brain going and kind of talk myself out of a full panic attack.”
“Everything in my body was failing and the one thing that seemed to be fully intact was my brain, which is always strange to me considering I had a brain illness and the damage was really catastrophic,” he adds.
Haendel remained in this state for 10 months, which he recalls being a brutal time. He was transferred to hospice care; however, he was eventually admitted back to the hospital because insurance only covered six months of care.
“I wasn't dying, but I wasn't getting better, which was a frightening thought,” he shares. “I kept overhearing them say I wouldn't make it out of this state. And I was like, ‘Oh my god. I could be stuck like this forever,’ which was actually more terrifying than dying.”
In June 2018, Haendel was transferred from hospice care back to Mass Gen’s neuro ICU. While there, he experienced the first glimpse of hope that he’d come out of locked-in syndrome.
“Around 4th of July, I heard the familiar voice of Dr. Levinson, who was in charge of my complex care. He was like, ‘You guys see that? He's moving something.’ And the other doctors were like, ‘No, that's involuntary.’”
“It was the first time medical staff had talked to me directly in a while. He just said, ‘Hey, I don't know if you can hear me, but if you can, do that again.’ I kind of had this rush go through me and I was like, ‘Wow, this is my one and only shot. I don't even know what I moved, but just do something,’” he recalls. “I tensed up my entire body and I didn't think it was working, but then I heard, ‘Wow, he is actually doing it.’”
Haendel’s doctors immediately brought in a specialist in nonverbal augmented speech therapy, who started working with him regularly to relearn how to blink. Over the next two weeks, he was able to blink. Medical staff then created a system where he was able to communicate yes and no by blinking and sticking out his tongue, which eventually progressed to him using a letter board to create sentences. “The first thing I spelled out was, ‘I can hear you,’” he says.
One day, Haendel recalls overhearing a conversation about moving him to a rehabilitation facility.
“I heard crosstalk of how I wouldn't be accepted because I can't participate in the mandatory three hours of physical, occupational and speech therapy. I could only participate in speech. I started freaking out. I heard my heart machine going off.”
“They were like, ‘Calm down, calm down. Do you want to use the letter board?’ And I just spelled out ‘I can do three hours.’ I heard them say, ‘Oh my God, he's actually tracking our conversations.’ And that was really the moment they realized how intact I was. And that was when I first felt like, okay, they actually know I'm in here.”
Days later Haendel was transferred to Spaulding Rehabilitation Hospital in Boston. “It was very motivating for me and at that point I was like, I am going to do everything in my power to get out of this.”
The next few years were a “very grueling, slow process,” as Haendel went through intense therapy retraining his brain to communicate with his body at Western Massachusetts Hospital.
“I thought I'd been through the worst. Not that it was any worse than being locked in, but it was a new type of pain that I hadn't experienced,” he explains on his recovery. “It was quite bad, but I kept telling myself if you want to get out of the hospital, if you want to have a life again, this is what it takes.”
By 2019, Haendel started coming out of his paralysis and making baby sounds. The following year, he started talking in sentences and was able to get out of bed and into a wheelchair for the first time.
In December 2020, he officially returned home and has since been doing outpatient therapy, which he will continue as his recovery remains ongoing.
“Now, I'm walking with a walker at home. I can also transfer in and out of cars. I navigate my community on a scooter, but in therapy I'm using a cane. I can also feed myself and hydrate myself,” he says. “In 2021, I was still not able to take care of myself whatsoever. And in the last year I've been able to take care of myself.”
Haendel, who is now divorced, says it’s unbelievable that he’s come so far in his recovery. He’s been sharing his journey on social media to help others understand the importance of determination when things get tough. The 36-year-old also co-founded an accessibility-focused app, Ahoi, which helps users find places that meet their specific needs like accessible parking, entry ramps, elevators, automatic doors, etc.
“I have such a different perspective on what's important in life. And going through what I went through has definitely made me stronger,” he tells PEOPLE. “It feels amazing and a big part of why I'm telling my story and have this company is to help people and help the world.”
“I want people to not give up in recovery when they hear they have terminal disease,” Haendel says. “That's a lot of what I want to do with my life now is just help and motivate people.”
https://people.com/man-declared-brain-dead-talks-locked-in-syndrome-recovery-exclusive-8740104
Macchi ZA, Carlisle TC, Filley CM. Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review. J Neurol Sci. 2022 Nov 15;442:120420. doi: 10.1016/j.jns.2022.120420. Epub 2022 Sep 13. PMID: 36156344; PMCID: PMC11008924.
Abstract
Objectives:
Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL.
Methods:
A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥4 weeks follow-up with neuroimaging consistent with TL.
Results:
Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery.
Conclusion:
Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.
In May 2017, Haendel noticed that his voice started to become higher pitched than normal. Initially brushing it off, it wasn’t until he started having balance issues that he decided to visit the emergency room on Memorial Day weekend.
Doctors believed he was having stroke-like symptoms, so he was admitted and given IV fluids. Haendel, now 36, had been to the hospital many times before and expected to be monitored for a few hours and then simply sent home with antibiotics. And he was right.
“They were actually about to discharge me when my wife came in and said, ‘You cannot discharge him. This is not my husband.’ She played an old voicemail for them. My voice and the voice I had been using were completely different,” he tells PEOPLE. “So the doctors and nurses and emergency room staff were like, ‘Whoa,’ and ordered an emergency MRI.”
One day later, Haendel was diagnosed with acute toxic leukoencephalopathy (ATL), a rare and often fatal brain disease caused by exposure to toxic substances. He was given six months to live.
“I woke up and there was a whole team of people in the room,” he recalls. “A doctor was sitting on the
Haendel immediately thought about his late mother, who died of breast cancer when he was 19. He remembered watching her struggle to fight the disease for 10 years before her death, a time where he struggled mentally and turned to drugs to cope.
Doctors told Haendel that in his case, the ATL was attributed to that past substance abuse. “I literally said out loud, ‘I am f—ed.’ My first thought was how disappointed my mom would be in me,” he says. “There were very powerful emotions all at once.”
“I told my wife, ‘I watched my mom die. You shouldn't have to watch me die,’” he adds.
After revealing his diagnosis, doctors pulled out a whiteboard and broke down exactly how Haendel’s disease was expected to progress. The first month he wouldn’t be able to walk, even with the help of assistive devices. Month two, he would be confined to a wheelchair until he’s unable to tolerate it due to chronic pain. By month three, he would be bedridden and lose the ability to eat, swallow and talk. In the fourth and final stage of the disease, he would slip into a coma and eventually die.
“And no one had ever survived stage four,” Haendel says.
Unfortunately, Haendel’s doctors were “right on the money with that timeframe,” and his health took a turn for the worst. “I underestimated the amount of pain I would be in,” he admits, comparing his body to a car that’s gone haywire.
By November, Haendel’s speech was fully gone. He was admitted to the neuro ICU at Massachusetts General Hospital as he continued to deteriorate. Around this time, he slipped into what doctors believed was a coma, which was consistent with the natural progression of the disease.
December 1, 2017 was the first time he heard someone refer to him as brain dead.
“One of the doctors told my wife, ‘We're really sorry Mrs. Haendel, but your husband will not make it to Christmas.’ In my head, I was bummed because I had no illusion that I was going to die. But I'm in so much pain that it was also a relief that this constant struggle was going to be over,” he explains.
“But then I heard them say I was brain dead and it's time to start considering withdrawing life support. I was contemplating, am I brain dead? How can I think, how do I have memories?” he continues. “So even though I was having those thoughts that this is going to be over soon, I was like, ‘Oh, don't do that, I'm still in here.’”
Haendel appeared to be in a vegetative state. However, unknown to his doctors, his disease triggered locked-in syndrome, a rare and serious neurological disorder where damage to the brain stem leads to complete paralysis over all voluntary muscles except for the ones that control the eyes, according to the National Organization for Rare Disorders (NORD). While he can still feel touch, pain, an itch and other sensations, and he is entirely aware of his environment and surroundings, Haendel is “locked” inside his body, as the name of the syndrome implies.
“It was the worst you can imagine,” he explains. “It was like being a prisoner in solitary confinement, but worse. You're totally paralyzed, you can't move, talk or signal. I was just talking to myself in my head. It was more of survival to keep my brain going and kind of talk myself out of a full panic attack.”
“Everything in my body was failing and the one thing that seemed to be fully intact was my brain, which is always strange to me considering I had a brain illness and the damage was really catastrophic,” he adds.
Haendel remained in this state for 10 months, which he recalls being a brutal time. He was transferred to hospice care; however, he was eventually admitted back to the hospital because insurance only covered six months of care.
“I wasn't dying, but I wasn't getting better, which was a frightening thought,” he shares. “I kept overhearing them say I wouldn't make it out of this state. And I was like, ‘Oh my god. I could be stuck like this forever,’ which was actually more terrifying than dying.”
In June 2018, Haendel was transferred from hospice care back to Mass Gen’s neuro ICU. While there, he experienced the first glimpse of hope that he’d come out of locked-in syndrome.
“Around 4th of July, I heard the familiar voice of Dr. Levinson, who was in charge of my complex care. He was like, ‘You guys see that? He's moving something.’ And the other doctors were like, ‘No, that's involuntary.’”
“It was the first time medical staff had talked to me directly in a while. He just said, ‘Hey, I don't know if you can hear me, but if you can, do that again.’ I kind of had this rush go through me and I was like, ‘Wow, this is my one and only shot. I don't even know what I moved, but just do something,’” he recalls. “I tensed up my entire body and I didn't think it was working, but then I heard, ‘Wow, he is actually doing it.’”
Haendel’s doctors immediately brought in a specialist in nonverbal augmented speech therapy, who started working with him regularly to relearn how to blink. Over the next two weeks, he was able to blink. Medical staff then created a system where he was able to communicate yes and no by blinking and sticking out his tongue, which eventually progressed to him using a letter board to create sentences. “The first thing I spelled out was, ‘I can hear you,’” he says.
One day, Haendel recalls overhearing a conversation about moving him to a rehabilitation facility.
“I heard crosstalk of how I wouldn't be accepted because I can't participate in the mandatory three hours of physical, occupational and speech therapy. I could only participate in speech. I started freaking out. I heard my heart machine going off.”
“They were like, ‘Calm down, calm down. Do you want to use the letter board?’ And I just spelled out ‘I can do three hours.’ I heard them say, ‘Oh my God, he's actually tracking our conversations.’ And that was really the moment they realized how intact I was. And that was when I first felt like, okay, they actually know I'm in here.”
Days later Haendel was transferred to Spaulding Rehabilitation Hospital in Boston. “It was very motivating for me and at that point I was like, I am going to do everything in my power to get out of this.”
The next few years were a “very grueling, slow process,” as Haendel went through intense therapy retraining his brain to communicate with his body at Western Massachusetts Hospital.
“I thought I'd been through the worst. Not that it was any worse than being locked in, but it was a new type of pain that I hadn't experienced,” he explains on his recovery. “It was quite bad, but I kept telling myself if you want to get out of the hospital, if you want to have a life again, this is what it takes.”
By 2019, Haendel started coming out of his paralysis and making baby sounds. The following year, he started talking in sentences and was able to get out of bed and into a wheelchair for the first time.
In December 2020, he officially returned home and has since been doing outpatient therapy, which he will continue as his recovery remains ongoing.
“Now, I'm walking with a walker at home. I can also transfer in and out of cars. I navigate my community on a scooter, but in therapy I'm using a cane. I can also feed myself and hydrate myself,” he says. “In 2021, I was still not able to take care of myself whatsoever. And in the last year I've been able to take care of myself.”
Haendel, who is now divorced, says it’s unbelievable that he’s come so far in his recovery. He’s been sharing his journey on social media to help others understand the importance of determination when things get tough. The 36-year-old also co-founded an accessibility-focused app, Ahoi, which helps users find places that meet their specific needs like accessible parking, entry ramps, elevators, automatic doors, etc.
“I have such a different perspective on what's important in life. And going through what I went through has definitely made me stronger,” he tells PEOPLE. “It feels amazing and a big part of why I'm telling my story and have this company is to help people and help the world.”
“I want people to not give up in recovery when they hear they have terminal disease,” Haendel says. “That's a lot of what I want to do with my life now is just help and motivate people.”
https://people.com/man-declared-brain-dead-talks-locked-in-syndrome-recovery-exclusive-8740104
Macchi ZA, Carlisle TC, Filley CM. Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review. J Neurol Sci. 2022 Nov 15;442:120420. doi: 10.1016/j.jns.2022.120420. Epub 2022 Sep 13. PMID: 36156344; PMCID: PMC11008924.
Abstract
Objectives:
Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL.
Methods:
A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥4 weeks follow-up with neuroimaging consistent with TL.
Results:
Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery.
Conclusion:
Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.
Wednesday, November 6, 2024
Clinical signatures of genetic epilepsies precede diagnosis in electronic medical records
Galer PD, Parthasarathy S, Xian J, McKee JL, Ruggiero SM, Ganesan S, Kaufman MC, Cohen SR, Haag S, Chen C, Ojemann WKS, Kim D, Wilmarth O, Vaidiswaran P, Sederman C, Ellis CA, Gonzalez AK, Boßelmann CM, Lal D, Sederman R, Lewis-Smith D, Litt B, Helbig I. Clinical Signatures of Genetic Epilepsies Precede Diagnosis in Electronic Medical Records of 32 000 Individuals. Genet Med. 2024101211. doi:10.1016/j.gim.2024.101211. PMID: 39011766
Purpose: An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records (EMRs). Methods: We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32 112 individuals with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict SCN1A-related disorders and any genetic diagnosis. Results: We identified 47 774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years prior to molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6 and 9 months increased the likelihood of a later molecular diagnosis fivefold (P < .0001, 95% CI = 3.55-7.42). A later diagnosis of SCN1A-related disorders (AUC = 0.91) or an overall positive genetic diagnosis (AUC = 0.82) could be reliably predicted using random forest models. Conclusion: Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated EMR analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.
Commentary on the above:
Li Y. Predicting Pediatric Genetic Epilepsy Through Electronic Medical Records: A Data-Driven Biomarker Discovery Approach. Epilepsy Currents. 2024;0(0). doi:10.1177/15357597241290322
With the goal to identify key clinical features linked to genetic epilepsy syndromes and predict genetic diagnoses, Galer et al extracted clinical notes from the electronic medical record (EMR) system of 32 112 individuals diagnosed with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies at the Children's Hospital of Philadelphia Care Network between 2010 and 2022. A customized natural language processing (NLP) pipeline was utilized to help extract clinical features in the form of Language System codes. These features were subsequently mapped onto the Human Phenotype Ontology and segmented into 3-month age bins for analysis. A conservative framework was developed to analyze only clinical notes before an individual's genetic diagnosis, with additional analysis using cumulative time binning. Furthermore, validation was conducted by collecting phenotype data from individuals with SCN1A-related epilepsy disorders and control groups in two different cohorts, analyzing the most significant neurological phenotypes associated with SCN1A-related epilepsy and employing random forest models for prediction. In their study, causative genetic etiologies were found in 38% of individuals with known or presumed genetic epilepsy, involving 271 unique genes, with 87 occurring in two or more individuals. The median time from the first neurological abnormality to genetic diagnosis was 1.4 years in their cohort. The earliest clinical feature associated with a genetic diagnosis occurred a median of 3.62 years before the median age of genetic diagnosis. Furthermore, broad clinical features that predict positive genetic diagnoses independent of molecular etiology were identified, including muscular hypotonia between 1 and 1.25 years, neurodevelopmental abnormality between 6 and 9 months, and neurodevelopmental delay between 6 and 9 months.
The study offers valuable insights into the clinical applicability of predictive models for genetic diagnoses in epilepsy. The utilization of NLP allows for the extraction of data from real-world observations, facilitating the mapping of clinical phenotype trajectories in genetic epilepsies over time. This not only tracks the natural history overtime but also enables the identification of novel pathognomonic clinical features. Such an approach is especially beneficial for rare genetic disorders, enabling the discovery of unprecedented details that may have been previously overlooked. Additionally, the study highlights the promising combination of NLP with machine learning models to identify significant clinical phenotypes. This integrated approach may aid in predicting genetic diagnoses at an earlier age, offering potential for the application of precision medicine in epilepsy care.
Early recognition of diagnosis and optimized treatment has been one of the fundamental objectives in medical care to improve patient outcomes and enhance overall healthcare cost-effectiveness. Large-scale modeling of EMR trajectories have been developed for various common medical conditions such as sepsis, heart failure, and cancer, among others. These models leverage current advancements in large language models and deep learning technologies to drive forward the field of precision medicine. While early diagnosis of genetic epilepsies is crucial for timely treatment, the practicality and cost-effectiveness of such an approach would need further research. It is anticipated that clinical features or a combination thereof could be utilized to identify patients highly likely to have a genetic cause, prompting further genetic testing for confirmation or even consideration of empirical treatment when genetic testing is not an option in resource-limited scenarios. However, there is a need for ongoing evaluation of the potential for false positive identifications within EMR systems based on this proposed algorithm. Additionally, the cost implications and overall cost-effectiveness of these approaches warrant further investigation.
Furthermore, when considering the application of these discoveries beyond SCN1A syndromes, integrating them into clinical practice may encounter limitations in generalizability resulting from data heterogeneity or data insufficiency, which is one of the common challenges for prediction models based on EMR trajectories. The algorithms trained on pediatric epilepsy patients within a tertiary center network may present variations in specific terms or syndromes compared to the documentation practices of general neurologists or adult neurologists. These discrepancies could be from less detailed history reviews by general providers or inadequate data due to recall bias among patients and their guardians, ultimately leading to underdocumented clinical symptoms. For instance, specific symptoms like muscular hypotonia at a younger age between 1 and 1.25 years, identified as an independent clinical biomarker for genetic epilepsy diagnosis in this study, might not be consistently recorded due to recall bias related to their remote occurrence within families in adult neurology practice. Additionally, adult-onset genetic epilepsies exhibit unique genetic mutations and clinical features that can notably differ from those observed in childhood epilepsy cases. Therefore, further expansion of the training and application of similar methodologies across diverse populations holds significant promise in offering valuable insights in the field.
Purpose: An early genetic diagnosis can guide the time-sensitive treatment of individuals with genetic epilepsies. However, most genetic diagnoses occur long after disease onset. We aimed to identify early clinical features suggestive of genetic diagnoses in individuals with epilepsy through large-scale analysis of full-text electronic medical records (EMRs). Methods: We extracted 89 million time-stamped standardized clinical annotations using Natural Language Processing from 4,572,783 clinical notes from 32 112 individuals with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies. We applied these features to train random forest models to predict SCN1A-related disorders and any genetic diagnosis. Results: We identified 47 774 age-dependent associations of clinical features with genetic etiologies a median of 3.6 years prior to molecular diagnosis. Across all 710 genetic etiologies identified in our cohort, neurodevelopmental differences between 6 and 9 months increased the likelihood of a later molecular diagnosis fivefold (P < .0001, 95% CI = 3.55-7.42). A later diagnosis of SCN1A-related disorders (AUC = 0.91) or an overall positive genetic diagnosis (AUC = 0.82) could be reliably predicted using random forest models. Conclusion: Clinical features predictive of genetic epilepsies precede molecular diagnoses by up to several years in conditions with known precision treatments. An earlier diagnosis facilitated by automated EMR analysis has the potential for earlier targeted therapeutic strategies in the genetic epilepsies.
Commentary on the above:
Li Y. Predicting Pediatric Genetic Epilepsy Through Electronic Medical Records: A Data-Driven Biomarker Discovery Approach. Epilepsy Currents. 2024;0(0). doi:10.1177/15357597241290322
With the goal to identify key clinical features linked to genetic epilepsy syndromes and predict genetic diagnoses, Galer et al extracted clinical notes from the electronic medical record (EMR) system of 32 112 individuals diagnosed with childhood epilepsy, including 1925 individuals with known or presumed genetic epilepsies at the Children's Hospital of Philadelphia Care Network between 2010 and 2022. A customized natural language processing (NLP) pipeline was utilized to help extract clinical features in the form of Language System codes. These features were subsequently mapped onto the Human Phenotype Ontology and segmented into 3-month age bins for analysis. A conservative framework was developed to analyze only clinical notes before an individual's genetic diagnosis, with additional analysis using cumulative time binning. Furthermore, validation was conducted by collecting phenotype data from individuals with SCN1A-related epilepsy disorders and control groups in two different cohorts, analyzing the most significant neurological phenotypes associated with SCN1A-related epilepsy and employing random forest models for prediction. In their study, causative genetic etiologies were found in 38% of individuals with known or presumed genetic epilepsy, involving 271 unique genes, with 87 occurring in two or more individuals. The median time from the first neurological abnormality to genetic diagnosis was 1.4 years in their cohort. The earliest clinical feature associated with a genetic diagnosis occurred a median of 3.62 years before the median age of genetic diagnosis. Furthermore, broad clinical features that predict positive genetic diagnoses independent of molecular etiology were identified, including muscular hypotonia between 1 and 1.25 years, neurodevelopmental abnormality between 6 and 9 months, and neurodevelopmental delay between 6 and 9 months.
The study offers valuable insights into the clinical applicability of predictive models for genetic diagnoses in epilepsy. The utilization of NLP allows for the extraction of data from real-world observations, facilitating the mapping of clinical phenotype trajectories in genetic epilepsies over time. This not only tracks the natural history overtime but also enables the identification of novel pathognomonic clinical features. Such an approach is especially beneficial for rare genetic disorders, enabling the discovery of unprecedented details that may have been previously overlooked. Additionally, the study highlights the promising combination of NLP with machine learning models to identify significant clinical phenotypes. This integrated approach may aid in predicting genetic diagnoses at an earlier age, offering potential for the application of precision medicine in epilepsy care.
Early recognition of diagnosis and optimized treatment has been one of the fundamental objectives in medical care to improve patient outcomes and enhance overall healthcare cost-effectiveness. Large-scale modeling of EMR trajectories have been developed for various common medical conditions such as sepsis, heart failure, and cancer, among others. These models leverage current advancements in large language models and deep learning technologies to drive forward the field of precision medicine. While early diagnosis of genetic epilepsies is crucial for timely treatment, the practicality and cost-effectiveness of such an approach would need further research. It is anticipated that clinical features or a combination thereof could be utilized to identify patients highly likely to have a genetic cause, prompting further genetic testing for confirmation or even consideration of empirical treatment when genetic testing is not an option in resource-limited scenarios. However, there is a need for ongoing evaluation of the potential for false positive identifications within EMR systems based on this proposed algorithm. Additionally, the cost implications and overall cost-effectiveness of these approaches warrant further investigation.
Furthermore, when considering the application of these discoveries beyond SCN1A syndromes, integrating them into clinical practice may encounter limitations in generalizability resulting from data heterogeneity or data insufficiency, which is one of the common challenges for prediction models based on EMR trajectories. The algorithms trained on pediatric epilepsy patients within a tertiary center network may present variations in specific terms or syndromes compared to the documentation practices of general neurologists or adult neurologists. These discrepancies could be from less detailed history reviews by general providers or inadequate data due to recall bias among patients and their guardians, ultimately leading to underdocumented clinical symptoms. For instance, specific symptoms like muscular hypotonia at a younger age between 1 and 1.25 years, identified as an independent clinical biomarker for genetic epilepsy diagnosis in this study, might not be consistently recorded due to recall bias related to their remote occurrence within families in adult neurology practice. Additionally, adult-onset genetic epilepsies exhibit unique genetic mutations and clinical features that can notably differ from those observed in childhood epilepsy cases. Therefore, further expansion of the training and application of similar methodologies across diverse populations holds significant promise in offering valuable insights in the field.
The role of default mode network connectivity in the onset of FCD-related focal epilepsy
Macdonald-Laurs E, Warren AEL, Leventer RJ, Harvey, AS. Why Did My Seizures Start Now? Influences of Lesion Connectivity and Genetic Etiology on Age at Seizure Onset in Focal Epilepsy. Epilepsia, 2024,65(6):1644–1657. https://doi.org/10.1111/epi.17947
Objective: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity. Methods: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset. Results: Median age at seizure onset was 5.4 (interquartile range = 2–7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within the sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort. Significance: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.
Objective: Patients with focal, lesional epilepsy present with seizures at variable ages. Larger lesion size and overlap with sensorimotor or default mode network (DMN) have been associated with younger age at seizure onset in cohorts with mixed types of focal cortical dysplasia (FCD). Here, we studied determinants of age at seizure onset in patients with bottom-of-sulcus dysplasia (BOSD), a discrete type of FCD with highly localized epileptogenicity. Methods: Eighty-four patients (77% operated) with BOSD were studied. Demographic, histopathologic, and genetic findings were recorded. BOSD volume and anatomical, primary versus association, rostral versus caudal, and functional network locations were determined. Normative functional connectivity analyses were performed using each BOSD as a region of interest in resting-state functional magnetic resonance imaging data of healthy children. Variables were correlated with age at seizure onset. Results: Median age at seizure onset was 5.4 (interquartile range = 2–7.9) years. Of 50 tested patients, 22 had somatic and nine had germline pathogenic mammalian target of rapamycin (mTOR) pathway variants. Younger age at seizure onset was associated with greater BOSD volume (p = .002), presence of a germline pathogenic variant (p = .04), DMN overlap (p = .04), and increased functional connectivity with the DMN (p < .05, false discovery rate corrected). Location within the sensorimotor cortex and networks was not associated with younger age at seizure onset in our relatively small but homogenous cohort. Significance: Greater lesion size, pathogenic mTOR pathway germline variants, and DMN connectivity are associated with younger age at seizure onset in small FCD. Our findings strengthen the suggested role of DMN connectivity in the onset of FCD-related focal epilepsy and reveal novel contributions of genetic etiology.
Recurrent status epilepticus episodes
Bauer K, Rosenow F, Knake S, Willems LM, Kämppi L, Strzelczyk A. Clinical Characteristics and Outcomes of Patients With Recurrent Status Epilepticus Episodes. Neurol Res Pract. 2023;5(1):34. doi:https://doi.org/10.1186/s42466-023-00261-9
Abstract
Background:
Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses.
Methods:
In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection.
Results:
We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients.
Conclusions:
This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.
Commentary on the above:
Gaspard N. Double, Double Toil and Trouble: Recurrent Episodes of Status Epilepticus Are Associated With Increasingly Worse Outcomes. Epilepsy Currents. 2024;24(5):316-317. doi:10.1177/15357597231223587
The first key finding is that 10% of patients with a first episode of SE are at risk of suffering from a recurrent episode of SE, half of them within 6 months of the first episode. This figure is roughly in line with the available literature, which provides an estimate of recurrence ranging from 7.6% to 32%. Thus, the annual risk of a second episode of SE after having suffered from a first is at least 250 to 1000 times higher than the annual incidence of SE in the general population. Even though half of the episodes of SE occur in patients with epilepsy, a 10% annual risk is still higher than the risk of SE in patients with epilepsy.
This indicates an intrinsic predisposition of a subgroup of patients for their seizures to present as SE. The International League Against Epilepsy defines SE as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures.” While these mechanisms still elude us, an individual’s predisposition for SE suggests that this could be identified by investigating patients with recurrent episodes, at the neuroanatomical, neurophysiological, and, perhaps, genetic levels. The mean age of patients in the cohort was 62 years at the time of the first episode and 63 years at the time of the second episode. This is not surprising as SE incidence peaks after 60 years. Part of it is explained by the higher incidence of acute brain injuries, such as ischemic strokes and cerebral hemorrhages, that can cause SE after 60 years. Since most patients in this cohort, and in other cohorts of recurrent SE, had remote epilepsy, it is also possible that this higher risk of SE and of SE recurrence is also in part explained by the aging of the brain, which could be accompanied by a decrease in the efficiency of the mechanisms responsible for seizure termination. The risk of SE is also higher in patients with drug-resistant epilepsy and uncontrolled seizures than in patients with controlled epilepsy. Whether this also affects the risk of recurrence is unclear, although a prior study found that recurrent episodes of SE were more likely in patients who took more anti-seizure medications (ASMs).
A few patients in the cohort suffered 3 or more episodes of SE. From the data presented in the article, it can be estimated that the risk of third, fourth, or fifth episode approximates 50%, which is even greater than the risk of a first recurrence. This might mean that some individuals have a particularly strong intrinsic predisposition for SE. Another possible explanation is that each SE episode durably tampers the epileptic network to make it more prone to subsequent episodes. After all, the epileptogenic effects of SE are well-known: experimental SE, by chemical or electrical mean, is a classical way to cause epilepsy in animal models and acute symptomatic SE in acute brain injuries carries a greater risk of long-term post-injury epilepsy than single acute symptomatic seizures.
The second key finding of the study is that recurring episodes of SE are associated with increasingly worse outcomes. Compared to a first episode, a second episode of SE carries a higher risk of functional decline and dependency. It also leads to an increase in the burden of anti-seizure medications, including with medications that have a less desirable profile of side effects in the elderly, such as phenytoin and valproate. However, at the time of the second episode, the mean number of ASMs taken was lower than immediately after the first episode. Although this was not formally assessed in this study, ASM withdrawal was previously identified a precipitating factor of recurrent SE. The authors thus rightfully warn us against the temptation to quickly withdraw the ASM used to manage SE. Given the risk of recurrence, seizure action plans that could be used in the out-of-hospital setting should be discussed with patients and caregivers. Such plans may include fats-acting benzodiazepines for prolonged seizures.
There was also a trend toward increasing refractoriness at the time of the second episode. Of note, this has not been found in all other studies, perhaps owing to the difference in inclusion criteria mentioned above. A prior study found that the risk of refractoriness was higher if SE episodes recurred within 6 months of the first episode, but this was probably explained a greater proportion of acute and progressive etiologies in this subgroup.
Abstract
Background:
Multiple studies have focused on medical and pharmacological treatments and outcome predictors of patients with status epilepticus (SE). However, a sufficient understanding of recurrent episodes of SE is lacking. Therefore, we reviewed recurrent SE episodes to investigate their clinical characteristics and outcomes in patients with relapses.
Methods:
In this retrospective, multicenter study, we reviewed recurrent SE patient data covering 2011 to 2017 from the university hospitals of Frankfurt and Marburg, Germany. Clinical characteristics and outcome variables were compared among the first and subsequent SE episodes using a standardized form for data collection.
Results:
We identified 120 recurrent SE episodes in 80 patients (10.2% of all 1177 episodes). The mean age at the first SE episode was 62.2 years (median 66.5; SD 19.3; range 21–91), and 42 of these patients were male (52.5%). A mean of 262.4 days passed between the first and the second episode. Tonic–clonic seizure semiology and a cerebrovascular disease etiology were predominant in initial and recurrent episodes. After subsequent episodes, patients showed increased disability as indicated by the modified Rankin Scale (mRS), and 9 out of 80 patients died during the second episode (11.3%). Increases in refractory and super-refractory SE (RSE and SRSE, respectively) were noted during the second episode, and the occurrence of a non-refractory SE (NRSE) during the first SE episode did not necessarily provide a protective marker for subsequent non-refractory episodes. An increase in the use of intravenous-available anti-seizure medication (ASM) was observed in the treatment of SE patients. Patients were discharged from hospital with a mean of 2.8 ± 1.0 ASMs after the second SE episode and 2.1 ± 1.2 ASMs after the first episode. Levetiracetam was the most common ASM used before admission and on discharge for SE patients.
Conclusions:
This retrospective, multicenter study used the mRS to demonstrate worsened outcomes of patients at consecutive SE episodes. ASM accumulations after subsequent SE episodes were registered over the study period. The study results underline the necessity for improved clinical follow-ups and outpatient care to reduce the health care burden from recurrent SE episodes.
Commentary on the above:
Gaspard N. Double, Double Toil and Trouble: Recurrent Episodes of Status Epilepticus Are Associated With Increasingly Worse Outcomes. Epilepsy Currents. 2024;24(5):316-317. doi:10.1177/15357597231223587
The first key finding is that 10% of patients with a first episode of SE are at risk of suffering from a recurrent episode of SE, half of them within 6 months of the first episode. This figure is roughly in line with the available literature, which provides an estimate of recurrence ranging from 7.6% to 32%. Thus, the annual risk of a second episode of SE after having suffered from a first is at least 250 to 1000 times higher than the annual incidence of SE in the general population. Even though half of the episodes of SE occur in patients with epilepsy, a 10% annual risk is still higher than the risk of SE in patients with epilepsy.
This indicates an intrinsic predisposition of a subgroup of patients for their seizures to present as SE. The International League Against Epilepsy defines SE as “a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures.” While these mechanisms still elude us, an individual’s predisposition for SE suggests that this could be identified by investigating patients with recurrent episodes, at the neuroanatomical, neurophysiological, and, perhaps, genetic levels. The mean age of patients in the cohort was 62 years at the time of the first episode and 63 years at the time of the second episode. This is not surprising as SE incidence peaks after 60 years. Part of it is explained by the higher incidence of acute brain injuries, such as ischemic strokes and cerebral hemorrhages, that can cause SE after 60 years. Since most patients in this cohort, and in other cohorts of recurrent SE, had remote epilepsy, it is also possible that this higher risk of SE and of SE recurrence is also in part explained by the aging of the brain, which could be accompanied by a decrease in the efficiency of the mechanisms responsible for seizure termination. The risk of SE is also higher in patients with drug-resistant epilepsy and uncontrolled seizures than in patients with controlled epilepsy. Whether this also affects the risk of recurrence is unclear, although a prior study found that recurrent episodes of SE were more likely in patients who took more anti-seizure medications (ASMs).
A few patients in the cohort suffered 3 or more episodes of SE. From the data presented in the article, it can be estimated that the risk of third, fourth, or fifth episode approximates 50%, which is even greater than the risk of a first recurrence. This might mean that some individuals have a particularly strong intrinsic predisposition for SE. Another possible explanation is that each SE episode durably tampers the epileptic network to make it more prone to subsequent episodes. After all, the epileptogenic effects of SE are well-known: experimental SE, by chemical or electrical mean, is a classical way to cause epilepsy in animal models and acute symptomatic SE in acute brain injuries carries a greater risk of long-term post-injury epilepsy than single acute symptomatic seizures.
The second key finding of the study is that recurring episodes of SE are associated with increasingly worse outcomes. Compared to a first episode, a second episode of SE carries a higher risk of functional decline and dependency. It also leads to an increase in the burden of anti-seizure medications, including with medications that have a less desirable profile of side effects in the elderly, such as phenytoin and valproate. However, at the time of the second episode, the mean number of ASMs taken was lower than immediately after the first episode. Although this was not formally assessed in this study, ASM withdrawal was previously identified a precipitating factor of recurrent SE. The authors thus rightfully warn us against the temptation to quickly withdraw the ASM used to manage SE. Given the risk of recurrence, seizure action plans that could be used in the out-of-hospital setting should be discussed with patients and caregivers. Such plans may include fats-acting benzodiazepines for prolonged seizures.
There was also a trend toward increasing refractoriness at the time of the second episode. Of note, this has not been found in all other studies, perhaps owing to the difference in inclusion criteria mentioned above. A prior study found that the risk of refractoriness was higher if SE episodes recurred within 6 months of the first episode, but this was probably explained a greater proportion of acute and progressive etiologies in this subgroup.
Tuesday, November 5, 2024
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