Friday, December 29, 2023

New genetic link found for some forms of SIDS

Miklas JW, Clark E, Levy S, Detraux D, Leonard A, Beussman K, Showalter MR, Smith AT, Hofsteen P, Yang X, Macadangdang J, Manninen T, Raftery D, Madan A, Suomalainen A, Kim DH, Murry CE, Fiehn O, Sniadecki NJ, Wang Y, Ruohola-Baker H. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun. 2019 Oct 11;10(1):4671. doi: 10.1038/s41467-019-12482-1. Erratum in: Nat Commun. 2020 May 8;11(1):2387. PMID: 31604922; PMCID: PMC6789043.

Miklas JW, Clark E, Levy S, Detraux D, Leonard A, Beussman K, Showalter MR, Smith AT, Hofsteen P, Yang X, Macadangdang J, Manninen T, Raftery D, Madan A, Suomalainen A, Kim DH, Murry CE, Fiehn O, Sniadecki NJ, Wang Y, Ruohola-Baker H. Author Correction: TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun. 2020 May 8;11(1):2387. doi: 10.1038/s41467-020-16186-9. Erratum for: Nat Commun. 2019 Oct 11;10(1):4671. PMID: 32385292; PMCID: PMC7210873.


Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.


New genetic link found for some forms of SIDS

Newborns with this genetic mutation succumb suddenly to heart failure because they are unable to process milk.

A genetic link has now been found for some instances of Sudden Infant Death Syndrome, or SIDS. The new UW Medicine research study is the first such to make an explainable link tracking the mechanism between a genetic anomaly and some forms of the devastating syndrome, which claims the lives of more than 3,000 infants a year.

Hannele Ruohola-Baker, professor of biochemistry at the University of Washington School of Medicine, headed the multi-institutional study. The findings are published in the Oct. 11 ediition of Nature Communications. See the paper. The research focused on mitochondrial tri-functional protein deficiency, a potentially fatal cardiac metabolic disorder caused by a genetic mutation in the gene HADHA.

Newborns with this genetic anomaly can’t metabolize the lipids found in milk, and die suddenly of cardiac arrest when they are a couple months old. Lipids are a category of molecules that include fats, cholesterol and fatty acids.

“There are multiple causes for sudden infant death syndrome,” said Ruohola-Baker, who is also associate director of the UW Medicine Institute for Stem Cell and Regenerative Medicine, where the lab she heads is located. “There are some causes which are environmental. But what we’re studying here is really a genetic cause of SIDS. In this particular case, it involves defect in the enzyme that breaks down fat.”

Jason Miklas, who earned his Ph.D. at the UW and is now a postdoctoral fellow at Stanford University, was the lead author on the paper. He said he first came up with the idea while researching heart disease. He noticed a small research study that had examined children who couldn’t process fats and who had cardiac disease that could not be readily explained.

So Miklas, along with Ruohola-Baker, started looking into why heart cells, grown to mimic infant cells, were dying in the petri dish where they were being grown.

“If a child has a mutation, depending on the mutation the first few months of life can be very scary as the child may die suddenly,” he noted. “An autopsy wouldn’t necessarily pick up why the child passed but we think it might be due to the infant’s heart stopping to beat.”

“We’re no longer just trying to treat the symptoms of the disease,” Miklas added. “We’re trying find ways to treat the root problem. It’s very gratifying to see that we can make real progress in the lab toward interventions that could one day make their way to the clinic.”

In MTP deficiency, the heart cells of affected infants do not convert fats into nutrients properly, This results in a build-up of unprocessed fatty material that can disrupt heart functions. More technically, the breakdown occurs when enzymes fail to complete a process known as fatty acid oxidation. It is possible to screen for the genetic markers of MTP deficiency; but effective treatments are still a ways off.

Ruohola-Baker sees the latest laboratory discovery as a big step towards finding ways to overcome SIDS.

“There is no cure for this,” she said. “But there is now hope, because we’ve found a new aspect of this disease that will innovate generations of novel small molecules and designed proteins, which might help these patients in the future.”

One drug the group is focusing on now is Elamipretide, a drug used to stimulate hearts and organs that have oxygen deficiency, but was barely considered for helping infant hearts, until now. In addition, prospective parents can be screened now, to see if there is a chance that they could have a child who might carry this genetic mutation.

Ruohola-Baker has a personal interest in this research, as one of her friends in her home country of Finland had a baby who died of SIDS.

“It was absolutely devastating for that couple,” she said. “Since then, I’ve been very interested in the causes for Sudden Infant Death Syndrome. It’s very exciting to think that our work may contribute to future treatments, and help for the heartbreak for the parents who find their children have these mutations.”

This work was supported by the National Institutes of Health (1027 R01GM097372, R01GM083867, 1P01GM081619, 1028 R01HL135143, U01HL099997; UO1HL099993, F32 HL126332), the Academy of Finland, Finnish Foundation for Cardiovascular Research. Wellstone Muscular Dystrophy Cooperative Research Center, (U54AR065139), Natural Sciences and Engineering Research of Canada, Alexander Graham Bell Graduate Scholarship, and a National Science Foundation Fellowship.

Wednesday, December 27, 2023

Assisted death for the mentally ill

Under a new law that would go into effect in March, patients suffering from mental illness in Canada would be able to have access to an assisted death, according to the New York Times. 

Canada already offers the option to terminally and chronically ill patients.

Bill C-7, which passed in March 2021, acknowledged that "further consultation and deliberation are required to determine whether it is appropriate and, if so, how to provide medical assistance in dying (MAID) to persons whose sole underlying medical condition is a mental illness."

On February 2, 2023, the federal government announced plans to delay MAID eligibility for people whose sole medical condition is mental illness until March 17, 2024, according to Dying with Dignity Canada.

Dying With Dignity Canada is the national human-rights charity that says it is committed to improving the quality of dying, protecting end-of-life rights and helping Canadians avoid unwanted suffering. 

If the law passes, it would make Canada one of about half a dozen countries that allow the procedure for that type of illness.

Prime Minister Justin Trudeau and his administration have been criticized for the new policy since it was announced, with some members of the Conservative Party accusing the government of promoting a "culture of death." 

An Ipsos poll, commissioned by Dying With Dignity Canada in 2023, showed that a strong majority of people in Canada, nearly 80%, support the bill.

Supporters claim denying mentally ill people access to the same humane option to end their suffering amounts to discrimination. 

Parliament has delayed adding mental illness as an option to receive an assisted death for the past three years over concerns about how they can administer it and added that it could get delayed again. Canada’s existing assisted death law only applies to people who are terminally ill or living with physical disabilities or chronic, incurable conditions.

In 2015, Canada's Supreme Court decriminalized assisted death, claiming that forcing Canadians to live with intolerable suffering violates fundamental rights to liberty and security.

According to a report by the federal health ministry, over 13,000 Canadians had an assisted death last year, which totaled a 31% increase from the previous year. The report showed that of those numbers, 463 people were not actually terminally ill, but suffered from other medical conditions. 

According to the Times, a person seeking assisted death would have to be evaluated, and their condition determined to be "irremediable."

Fox News Digital reached out to Dying with Dignity Canada for comment on this story, but has back yet heard back.

Tuesday, December 19, 2023

My tics and Tourette's syndrome modus operandi

 A walk down memory lane. After 8 1/2 more years, my perspective still hasn't changed.

Monday, December 18, 2023

Baylen Dupree with Tourette syndrome

Laughter is the best medicine

It's a miracle — and it all started with a joke.

As Jennifer Flewellen, of Niles, Michigan, lay motionless in a hospital bed last year, stuck in a nearly five-year coma caused by a car crash, her mother Peggy Means told her a joke. Then the impossible happened: Flewellen, 41, laughed.

"When she woke up, it scared me at first because she was laughing and she had never done that," Means tells PEOPLE. "Every dream came true. Today's the day I said, 'That door that was closed, that kept us apart, had just opened. We were back.'"

The August 2022 breakthrough was just the first step in a long battle for Flewellen, who is working hard to regain her speech and mobility after being in a cocoon state where time ceased as her brain slowly healed.  

“She woke up, but she didn't completely. She couldn't speak, but she was nodding,” Means, 60, says. “She would still sleep a lot right at first, but then as the months would go by, she would get stronger and be more awake.”

“This is so rare,” Dr. Ralph Wang, her physician at Michigan’s Mary Free Bed Rehabilitation Hospital, tells PEOPLE. “Not just waking up, but making progress. Maybe 1-3% of patients wake up and make progress this far out.”

The feisty mom reached another big goal in October when she was able to participate in a senior night football celebration with youngest son Julian, 17, at a Niles High School football game.

“She was my biggest supporter,” says Julian, who was 11 when his mom fell into a coma. “So to have my biggest supporter back on the sidelines cheering me on, it was a surreal moment."

After news hit about her attending her son's football game, Flewellen was able to secure additional therapy through Mary Free Bed, a local rehabilitation hospital.

In a PEOPLE video interview with her mom from the rehabilitation hospital, an animated Flewellen, who can only string a few words together, nods yes and no to questions and sits up almost straight in a portable hospital bed.

Flewellen's nightmare-turned-miracle began with a typical morning on Monday, Sept. 25, 2017. Then a 35-year-old wife and mother of three young boys in the small town of Niles, Flewellen had just dropped off her three sons at school and was heading to work at Bittersweet Pet Resorts.

It was the last typical morning she would have.  At 8:23 a.m., she hit a utility pole, according to a news report from local radio station WSJM. (Neither speed nor alcohol appeared to be factors in the crash that left her unresponsive.)

Flewellen remained in a coma for almost five years, during which time her mom Peggy — who only recently retired from her job — stayed by her side, visiting almost every day in the chance that her daughter would one day respond to her.

When it finally happened, Means recorded the moment and quickly sent the video to family and friends. The next day, Julian and his brothers went to the hospital.

“I told her I was Juju and her eyes lit up like, 'Wow, it's my Juju bean,'" Julian says, noting his nickname. “But when she actually found out our ages and things like that, it broke her heart. She started to cry.”

Julian says it wasn’t easy for his mom to learn he was a junior and that his brothers Skylar, now 21, and Daeton, 19, had already graduated from high school.

“We've talked about the time that she's missed, and we try not to, because it makes her upset,” Julian says. “But my grandma always tells her, 'You can't sit here and be sad because being sad is not going to get you moving forward.'"

Although Flewellen wasn't aware of her mom's near-daily visits, Means says that her during her daughter's recovery, she played her an audio book about a woman who had been in a coma and described it as a euphoric, peaceful and calming place.

“Jenn cried and said that’s how she felt, so that was nice to know,” Means says. “There were times I wanted to believe she knew I was there, but something just told me this was what I’ve got to do.”

At first, most friends and family didn’t believe Means when she said her daughter had come out of the coma. Worse, she says, were the hospital staff who didn't think Flewellen would progress much past simply waking up.

“I asked for therapy and they thought I was crazy, but she got speech therapy,” says the persistent mom. 

“You have to be a strong advocate,” she adds.

At first Flewellen couldn’t make a sound, but with the help of a little whistle, she was able to bring air up.

Next were vowels. Last Christmas, while her daughter was still living at the hospital, Means gave Flewellen a kitty named Huey “because it was vowels,” Means says with a smile as her daughter also grins.

This is just the beginning of Flewellen's new, post-coma life. Even though she still needs assistance in "almost everything," Dr. Wang says she's already exceeded expectations.

“If she can take a few steps, feed herself and communicate more, those would be huge wins,” Wang says. “Both she and her mom are wonderfully driven. In six months, if she was a 10 before, if we can get her to a four or five. That would be tremendous.”

Means believes her daughter will be walking soon and making up time with her boys.

When she's told that she looks ready to take on the world, Flewellen replies, "I am."

Courtesy of my daughter

Thursday, December 14, 2023

Child pornography charges

Dr. Brian Aalbers, DO, a pediatric neurology specialist, is charged in federal court complaint with one count of attempted production of child pornography.

Court documents stated that Oct. 23, 2023, Kansas City, Missouri, police officers were sent to meet a reporting party who said he located hidden video cameras. The location of where the officers were sent and other details were blacked out in a court document.

Aalbers arrived at the scene, but did not provide a statement, according to the court document.

The person who reported the hidden video cameras contacted KCMO police about text messages he received from Aalbers.

Officers found Aalbers in a Lenexa hotel and took him to Advent Health for voluntary treatment, the document states.

The hospital security staff took a backpack from Aalbers that contained laptop computers, iPad tablets and a cell phone.

Aalbers did not have access to the devices while in the facility and asked a friend to get his backpack.

According to the court document, Aalbers asked that person to destroy the devices because there was "bad stuff" on them.

In November, a forensic examiner told investigators there over 20,000 videos found on a MacBook Pro.

The videos were from December 2020 to October 2023.

A pediatric neurologist from Overland Park is currently under investigation for possessing and attempting to produce child pornography.

According to an affidavit, Dr. Brian Aalbers allegedly used hidden cameras to record thousands of videos.

However, it remains unclear where the cameras were located and whether any patients were recorded.

Many parents, whose children were patients of Aalbers, are shocked.

Sarah Howland, a mother whose two children saw Aalbers regularly at Overland Park Regional Medical Center and Lee's Summit Medical Center, expressed her concern.

"It's just really disturbing to think that someone who's such a great doctor and who is so knowledgeable and so smart like that has that other side to him," Howland said.

She also shared her frustration with the lack of communication from HCA Midwest Health, expecting more proactive communication regarding the investigation.

"You would have thought that they would have sent out something on a patient portal or something like, 'Hey, just so you know, you know, we don't have information, but your doctor is no longer going to be there' and you're probably going to see something about him in the news.'"

HCA Midwest Health released a statement, saying that there is no indication at this time that the allegations against Aalbers involved patients.

They also confirmed that Aalbers is no longer affiliated with Overland Park Regional Medical Center or any other facilities or clinics.

Thursday, December 7, 2023

UNC13A mutation as a cause of congenital myasthenia

Inspired by a patient

Ohno K, Ohkawara B, Shen XM, Selcen D, Engel AG. Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review. Int J Mol Sci. 2023 Feb 13;24(4):3730. doi: 10.3390/ijms24043730. PMID: 36835142; PMCID: PMC9961056.


Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

Wednesday, December 6, 2023

AP4S1 mutations

Inspired by a patient

Hardies K, May P, Djémié T, Tarta-Arsene O, Deconinck T, Craiu D; AR working group of the EuroEPINOMICS RES Consortium; Helbig I, Suls A, Balling R, Weckhuysen S, De Jonghe P, Hirst J. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet. 2015 Apr 15;24(8):2218-27. doi: 10.1093/hmg/ddu740. Epub 2014 Dec 30. PMID: 25552650; PMCID: PMC4380070.


We report two siblings with infantile onset seizures, severe developmental delay and spastic paraplegia, in whom whole-genome sequencing revealed compound heterozygous mutations in the AP4S1 gene, encoding the σ subunit of the adaptor protein complex 4 (AP-4). The effect of the predicted loss-of-function variants (p.Gln46Profs*9 and p.Arg97*) was further investigated in a patient's fibroblast cell line. We show that the premature stop mutations in AP4S1 result in a reduction of all AP-4 subunits and loss of AP-4 complex assembly. Recruitment of the AP-4 accessory protein tepsin, to the membrane was also abolished. In retrospect, the clinical phenotype in the family is consistent with previous reports of the AP-4 deficiency syndrome. Our study reports the second family with mutations in AP4S1 and describes the first two patients with loss of AP4S1 and seizures. We further discuss seizure phenotypes in reported patients, highlighting that seizures are part of the clinical manifestation of the AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.

Carmona S, Marecos C, Amorim M, Ferreira AC, Conceição C, Brás J, Duarte ST, Guerreiro R. AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria. Neurol Genet. 2018 Sep 19;4(5):e273. doi: 10.1212/NXG.0000000000000273. PMID: 30283821; PMCID: PMC6167175.


Hereditary spastic paraplegias (HSPs) are a group of rare inherited neurodegenerative disorders that result from primary retrograde dysfunction of the long descending fibers of the corticospinal tract, causing lower limb spasticity and muscular weakness. This group of diseases has a heterogeneous clinical presentation. An extensive list of associated genes, different inheritance patterns, and ages at onset have been reported in HSPs. Spastic paraplegia type 52 (SPG52) is an autosomal recessive disease caused by AP4S1 mutations. The disease is characterized by neonatal hypotonia that progresses to hypertonia and spasticity in early childhood, developmental delay, mental retardation, and poor or absent speech. Febrile or afebrile seizures may also occur.

Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. Erratum in: Brain. 2021 Apr 12;144(3):e33. PMID: 32979048; PMCID: PMC7780481.


Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Monday, December 4, 2023

Diagnosis by ChatGPT

A Boy Suffering Chronic Pain for 3 Years Finally Receives Correct Diagnosis from ChatGPT

The young boy dealt with chronic pain for years, forcing his mother to take him to see 17 specialists, none of whom could diagnose him

A mother has revealed how her son's three years of chronic pain and countless visits to medical specialists was finally solved after her prompts in ChatGPT unearthed the correct diagnosis.

During the COVID-19 lockdown, as reported by Today, Courtney, who didn't reveal her last name, purchased a bounce house to keep her young children entertained. Shortly after, her then-4-year-old son, Alex, began experiencing pain, with the family nanny informing Courtney, “I have to give [Alex] Motrin every day, or he has these gigantic meltdowns,” according to the outlet.

Courtney reportedly first took her son to the dentist when he started chewing things, with his parents concerned he was having issues with his molars or cavities.

This dentist appointment kicked off three years of visits with 17 different doctors in all manner of specialty fields.

“Our sweet personality ... (child) is dissolving into this tantruming crazy person that didn’t exist the rest of the time,” Courtney told Today.

The dentist suggested Alex see an orthodontist specializing in airway obstruction. While the orthodontist identified that Alex’s palate was too small for his mouth, making it tougher for him to breathe at night, the expander she placed in his palate only helped briefly.

“Everything was better for a little bit,” Courtney remembered. “We thought we were in the home stretch.”

A short time later, Courtney noticed her son had stopped growing. They reportedly visited a pediatrician, who suggested the pandemic had impacted Alex's growth, referring him to physical therapy due to imbalances between his left and right sides.

Around the time he was due to start physical therapy, Alex had been experiencing headaches, with a visit to a neurologist determining the youngster had migraines. He also saw an ear, nose, and throat specialist to see if his sleep problems were due to his sinus cavities.

“We saw so many doctors. We ended up in the ER at one point. I kept pushing,” Courtney told the outlet.

“Nobody’s willing to solve for the greater problem,” she added. “Nobody will even give you a clue about what the diagnosis could be.”

Frustrated Courtney was at the end of her rope when she said she made an account with the AI-powered bot program ChatGPT to share her son's symptoms and the information she had gathered from his prior magnetic resonance imaging.

“I went line by line of everything that was in his (MRI notes) and plugged it into ChatGPT,” she said. “I put the note in there about ... how he wouldn’t sit crisscross applesauce. To me, that was a huge trigger (that) a structural thing could be wrong.”

When ChatGPT suggested Alex was suffering from tethered cord syndrome, "it made a lot of sense," his mother admitted.

According to the American Association of Neurological Surgeons, tethered spinal cord syndrome is a neurologic disorder caused by tissue attachments that limit the movement of the spinal cord within the spinal column. These attachments cause an abnormal stretching of the spinal cord.

With this information provided by ChatGPT, Courtney found a Facebook group for families of children with tethered cord syndrome and was able to schedule an appointment with a neurosurgeon who examined Alex's MRI images and knew exactly what was wrong.

“She said point blank, ‘Here’s spinal bifida occulta, and here’s where the spine is tethered,' ” Courtney recalled.

When Alex was finally diagnosed, Courtney said she experienced "every emotion in the book, relief, validated, excitement for his future."

Following his diagnosis, Alex underwent surgery to fix his tethered cord syndrome, and while he is still recovering, Courtney said sharing his story may help other parents facing similar struggles, insisting that “you have to be your kid’s advocate.”

Controlled strokes to treat hemimegalencephaly

When Bella Hauschildt was born in August 2018, she looked like the average, healthy baby girl. But one day later, twitching in her eyes led to the discovery that the left side of her brain hid severe complications.

Bella had hemimegalencephaly, or HME, a rare disorder that causes half of the brain to grow overly large and abnormal, causing constant seizures.

“Bella was only a couple of days old. It was devastating news,” her grandmother, Ann Getting, said in a story with Children’s National Hospital in Washington, D.C., where Bella eventually went for treatment. “They told us about all kinds of potential disabilities. They also said it would be extremely difficult to control her seizures with medications.”

Because HME is so rare, there are few treatment methods. The typical approach is to open up the skull and remove half of the brain — the left side is not necessary to function normally — to eliminate the tissue that is causing the seizures. But they would have to wait until Bella was 3 months old to safely operate.

At that point, though, waiting was also too risky. Bella was already having 20 to 40 nonstop seizures each hour, even with seizure medication, and if they waited, her IQ would go down 10 to 20 points a month.

“Her seizures were so bad, her quality of life would have been negatively impacted if we waited,” her grandfather, David Getting, said.

The Gettings contacted a good friend, pediatrician Dr. Amy Mashburn, who got to work researching alternative treatments. That led her to Children’s National, where Dr. Taeun Chang, director of the Neonatal Neurology and Neonatal Neurocritical Care Program, had successfully treated a baby girl with the same disorder.

Instead of cutting into the baby’s brain, Chang and her fellow doctors instead purposefully induced repeated strokes to kill off the bad tissue that was causing seizures. Using a micro-catheter, Dr. Monica Pearl and her team go through the femoral artery in the thigh up to the blood vessels in the brain, and carefully put liquid embolic agents, a type of surgical glue, to block blood flow and force the tissue to die.

The procedure, being very new, also held risks, but the Gettings said it “didn’t take long” to decide on that option.

“You proceed with a treatment that offers more hope. You grab hope with both hands. You have the courage to try something that could have a much better outcome,” Ann said.

Before Bella turned 1 month old, the Children’s National team started inducing “controlled” strokes in her brain in three procedures spread out over several weeks. That successfully stopped 98 percent of the problems in her left brain.

Bella was adopted in October while she was still recovering at Children’s National and reliant on multiple seizure medications that made her lethargic.

“She was very sedated as her brain healed from the procedures,” Ambre Hauschildt, her adoptive mom, said. “She didn’t cry. She didn’t have any emotion and, because of the early brain damage, it wasn’t clear if she would ever show emotion. She was just a very quiet, very sleepy, very frail baby with a big question mark over her future.”

But Bella slowly improved, and doctors began to take down her medications, which snapped her out of the fog.

“She was smiling. She was crying. She was learning to suck her thumb. She was looking at us; her eyes would follow us,” Ambre said. “She was very much doing normal baby things: being fussy, wanting to be held — when she didn’t care before.”

Now 14 months old and at home in Iowa with Ambre and her adoptive father, Mark, Bella is down to three seizure medications and doing extremely well.

“She has not had a seizure since Dr. Chang did the procedures. No seizures. No side effects. You would never know she has epilepsy,” Ambre said. “It’s pretty amazing. We’re beyond proud of her. We celebrate all the little things: just seeing her hold her head up, learning to reach for things, and, of course, now she’s talking. She’s done all these things we didn’t know when or if she’d be able to do.”

Rasmussen's encephalitis

A 6-year-old girl with a rare neurological disease recently underwent surgery in Los Angeles that disconnected half of her brain.

Brianna Bodley, who was diagnosed with Rasmussen’s encephalitis in August 2022, is in recovery from the functional hemispherectomy on Sept. 28, according to a GoFundMe page organized by her mother Crystal Bodley.

The National Institute of Neurological Disorders and Stroke (NINDS) describes Rasmussen’s encephalitis (RE) as “a very rare, chronic inflammatory neurological disease that usually affect only one hemisphere (half) of the brain.”

Symptoms include frequent and severe seizures, inflammation of the brain (otherwise known as encephalitis), mental deterioration and the progressive loss of neurological functions such as motor skills, speech and mobility on one side of the body, per NINDS.

According to Brianna’s GoFundMe page, she was diagnosed with the disease after she was hospitalized twice within a month after experiencing several seizures at night.

Amid failure of several medications to stop the seizures, which damaged Brianna’s brain, it was recommended that she undergo the functional hemispherectomy. The surgery disconnects the brain hemispheres from each other, as “the only cure for the seizures caused by RE,” per her GoFundMe page.

“She was [in] pain due to her having non-stop seizures, which are shown in her leg that jerks all day long even when she’s sleeping,” Crystal wrote.

She also told ABC7 that her daughter’s “leg would bend up all the time and she would have trouble walking.”

Consequently, Dr. Richard Aaron Robison of Loma Linda University Health performed the 10-hour operation, telling ABC7, “Just disconnecting [the brain] is enough to stop the disease completely and essentially, potentially cure it.”

"Brianna will still be the same person, even after disconnecting half her brain," Robison explained to the outlet.

As of Oct. 3, Crystal wrote in an update on the GoFundMe page that Brianna’s medical team is focused on “pain management trying to help with her pain after surgery.” The 6-year-old will also start “intense rehab to learn how to walk and use her arm, speech therapy and more.”

According to the page, Brianna will be doing rehab until “she can walk and move her arm again,” but that she “will never get back her fine motor skills in her left hand and her peripheral view in her left eye.”

“She has a very long road of recovery, but she is a strong and determined little girl. I know she will do great things and overcome all of this,” her mother wrote.

Pediatric neurology in the post-Roe era

Gano D, Agarwal S, Khakoo Y. Pediatric Neurology in the Post-Roe Era. Pediatr Neurol. 2023 Dec;149:182-183. doi: 10.1016/j.pediatrneurol.2023.10.001. Epub 2023 Oct 6. PMID: 37913564.

No abstract available.

Sunday, December 3, 2023


When Mora Leeb was four months old, she began experiencing seizures. Her parents learned she had had a stroke in utero that had destroyed most of the left hemisphere of her brain and caused epilepsy. Medication wasn’t able to control the hundreds of seizures she was having every day, so her parents made the difficult decision to have Mora undergo a hemispherectomy: doctors removed the damaged tissue on the left side of her brain. Her right side has since had to adapt, taking on jobs normally done by the left, like speech and language. But with a circle of support and years of hard work, Mora is living a full life as a teenager in New Jersey. Mora and her family have shared their story in this week’s issue of PEOPLE magazine.

Mora Leeb walks through the doorway on a recent October afternoon with an energetic bounce. She stretches out her left arm for a hug. “Hi!” she says with a bright smile, turning to a table in front of her where a loaf of chocolate chip pumpkin bread is wrapped in tinfoil.

Before cutting into the bread, which she baked for the occasion, she has a joke for her visitor: “What do you call a writer that doesn’t follow sentence structure?” she asks. Much of her speech is slow, deliberate, almost robotic. Then the punchline tumbles out: “A rebel without a clause!” She follows with a laugh, and soon she’s dealing cards for a round of UNO FLIP!, which she plays (and wins) while munching on pumpkin bread.

It’s a charming but otherwise unremarkable introduction to this 16-year-old from South Orange, N.J., — until you understand the underlying triumph of the moment. Each ordinary action — walking, talking, reading a recipe, dealing cards, joking — has involved a painstaking learning process.

Mora has grown up without the use of the left side of her brain, after doctors removed it to stop the rampant seizures she experienced as an infant. Her right hemisphere has adapted to take on speech and language functions normally performed by the left, and she has had to push herself to use the weaker right side of her body.

“It blows my mind to think how far she’s come,” says Alexandra Clayton, director of therapy services at Intensive Therapeutics, a therapy center in West Caldwell, N.J., for children and young adults, where Mora has gone weekly since she was a toddler, unable to speak. “She’s one of the most determined people I know.”

But Mora, who has learned to ski and sing and play Sudoku, sees her success differently: “I don’t think what I’m doing is so amazing. Other people do these things too.”

A Shocking Discovery

When Mora was born in September 2007, “everyone said, ‘Here’s your beautiful little girl. Perfect,’” recalls her mom, Ann, 59, who thought her pregnancy had been normal and healthy. “It was a very happy time.”

Mora was the first child for Ann and her husband Seth, and they named her in honor of Ann’s father, Morris, who had died more than a decade earlier. “Mora means teacher in Hebrew,” says Ann. “When we selected her name, we had no idea how much Mora would teach us.”

For the first three months Mora made her milestones: She nursed; she rolled over; she smiled—and then it came to a standstill.

The seizures began when she was 4 months old, barely noticeable at first — but by February 2008 they were clustering 20 per minute, hundreds in a day. “When a baby's having seizures that are that frequent, the brain is not doing any of its normal functions,” says Dr. Prakash Kotagal, a pediatric epileptologist at Cleveland Clinic who has treated Mora. “Their development not only stagnates, but actually regresses.”

All of Mora’s milestones began to disappear and she was no longer smiling or rolling over. When doctors showed Ann and Seth, 55, scans of their daughter’s brain, “you didn’t need a medical degree to understand it. There were huge black areas in the left hemisphere,” Ann says. Mora’s severe epileptic seizures, they learned, had been caused by a massive stroke she had experienced in utero.

“A doctor explained that Mora’s brain had taken a pounding,” Ann says. The doctor told them if the damage and seizures could be contained to the left side, the right side could continue to function normally. “But there’s a large band of neurons that connects your left hemisphere to your right hemisphere called the corpus callosum,” Ann says. “And if the seizure activity migrates in some way across corpus callosum to the right, you're going to have a brain that really can't function at all.”

A Difficult Decision

Doctors tried to control the seizures with medication, but the drugs had little effect. A more drastic option was presented: surgery to remove the damaged half of their daughter’s brain — an operation known as a hemispherectomy. At first “we were stunned,” says Ann.

But the couple decided Mora’s best chance was surgery and they turned to Dr. William Bingaman, a neurosurgeon and head of epilepsy surgery at Cleveland Clinic. “If you stop the damaged hemisphere from seizing, you allow the good hemisphere to begin to develop, and patients are able to be at the best cognitively that they can be,” says Dr. Bingaman, who does up to 40 hemispherectomies each year. (About 150 are performed in the U.S. annually.).

In June 2008, when Mora was 9 months old, Dr. Bingaman and his team removed her damaged brain tissue. It was like a reset. “Mora was reborn for all the possibilities,” Ann says. “We are all about maximizing potential. We didn’t know what that could be for Mora, but we thought, ‘Let’s do what we can do.’”

For the Leebs, that has meant creating a circle of support around Mora with their other family members, in their synagogue, in their community and beyond. They sought advice from other families with children who had undergone hemispherectomies, and they quickly got Mora into speech and occupational therapy. “Life is not normal and it is hard work for Mora and her family,” says Dr. Kotagal. “But they've done a remarkable job. She has made remarkable progress.”

Mora's Hard Work

That progress hasn’t come easily or quickly for Mora. She began walking at 23 months, didn’t speak in sentences until she was 6, and she was 8 when she was learned to tie her own shoes.

She’s further challenged by the fact that her visual field is cut in half — she can't see out of the right side of each of her eyes. When Mora first came to Intensive Therapeutics at the age of 2, “she wasn't seeing her right hand, right arm, right leg. It wasn't being perceived,” explains Scott Matthews, founder of the center.

Each summer, Mora has participated in the center’s Camp Helping Hands, where Clayton, Mora’s primary occupational therapist since childhood, remembers meeting Mora. “Every day she would run through the door and go to the back left corner. We thought she was trying to escape, but she didn't know that that whole right side of the room was there,” she says. “She's learned to compensate for it and turn her head more.”

At the camp and during her weekly OT sessions, Mora has been pushed to use the weaker right side of her body with techniques like wearing a cast on her dominant left arm that forced her to use her right.

But everyday tasks for the teenager still take countless hours of practice. Two years ago, she mastered putting her own hair in a ponytail. “We worked tirelessly,” Alexandra Clayton says of the accomplishment.

A Scary Setback

Five years ago, Mora was about to tackle another big goal — riding a bike, an activity made all the more difficult by her restricted vision — when she had a medical setback. Her seizures returned and she again needed surgery. Her first operation was what is known as a “functional” hemispherectomy in which the left hemisphere was disconnected from the right and the damaged tissue was removed but some brain tissue was left intact. In August 2018, Dr. Bingaman’s team went back and removed the remaining tissue (spinal fluid fills the emptied cavity) in hopes that the seizures would stop.

“I was probably more concerned about Mora before the second surgery than the first,” says Ann. “Mora had come so far at that point – she was nearly 11 — and she was a person with her own style, sense of humor, charm. Would she regress in all the skills she possessed? Would something go wrong on the operating table? At her level of cognition, she needed explanations that she didn't need as a baby. Would we frighten her, traumatize her?”

But Mora managed to recover quickly and was even dancing at a family member’s wedding by December. “That's really a tribute to who she is. These things that I think would faze a lot of other people just don't seem to faze her that much,” Ann says.

Determined to Learn

Mora has continued to cope with medical complications — she is on anti-epileptic medication, she receives Botox injections in her right hand, arm and leg twice a year to keep her muscles loose and she lives with Crohn’s disease as well — but “through all of it, Mora has just kept going,” Ann says. “Yes sometimes, Seth and I would just want to throw in the towel and say enough already, but we keep going, too. How could we let Mora down?”

That steady support has been a big part of Mora’s success. “Mora really lucked out because her parents are people that aren’t ever going to give up,” says Dr. Bingaman. But, Seth says, he and Ann feel like the fortunate ones: “I feel very lucky. Mora is just fun to be with.”

Nearly three years after her second surgery, in 2021, Mora stood in front of her synagogue congregation, and hundreds of others tuning in via Zoom, to give her Bat Mizvah speech. “Personally, I can be described as a ‘glass half full’ girl,” she told the crowd. “There are challenges in my life. Things can be difficult. As a family we know that well, but we try to keep moving forward and hope for good times ahead.”

Mora remains committed to taking on challenges, including returning to difficult work of learning to riding a bike. “I am interested in learning most everything,” Mora says. And says Matthews, “the possibilities are endless if she puts her effort into it—and she will, because that’s who she is.”

Her 'Glass Half Full' Life

Today Mora is a ninth grader studying algebra, Spanish and chorus. Her bedroom, decorated in shades of pink and purple, is packed with books (a dictionary of antonyms, a book of idioms, a recent read, Best Wishes Book 1 by Sarah Mlynowsky), a collection of silly sunglasses adorned with pink flamingos, parrots and shamrocks, and a pillow on her bed that reads “Today is Going to be Altogether Awesome” — a prize for selling Girl Scouts cookies.

She proudly shows off her manicured bubblegum pink fingernails and her new sparkly pink earrings (getting her ears pierced was her 16th birthday present). On a recent outing, she went to see Taylor Swift; The Eras Tour concert film.

In so many ways, Mora is a typical teen, but her communication skills are still very slow which means it can be difficult for her to make close friends. “If you're a teenager and you want immediate answers, you're not going to get it from her,” says Seth, an architect who owns his own firm. But “you'll get the answer if you're patient. And we don't want things dumbed down. You don't have to treat her like a four-year-old. You just have to be patient with a 16-year-old.”

In person, she can expertly explain the rules for UNO FLIP! and how she packs up the thousand-plus Girl Scouts cookies she sells every year (each with a personal note to the buyer). But abstract questions are harder to process and elicit long pauses — and sometimes only silence. Given time, however, she responds thoughtfully, in a series of videos she sends later. “She won’t give up on things,” Seth says. “She never talks about her weaknesses. She will often say, ‘I can do this.’ And she’ll work at it to do it.”

When she’s not taking tennis lessons (she started learning in 2017) or reading a favorite book (a dictionary of 700 idioms is top of the list), Mora spends time helping researchers understand how the brain can adapt to trauma.

The Leebs were connected with several of the researchers through a group called the Pediatric Epilepsy Surgery Alliance, which provides support for families, advocates for research and offers an epilepsy surgery registry where families like the Leebs can share their experiences. “When you talk to a doctor about hemispheric surgery and ask, ‘How will my child be afterwards?’ most of the time they'll say, ‘We really don’t know all the long-term side effects of surgery,” says alliance founder and executive director Monika Jones. “Now we’re starting to inform the clinical community.”

Mora has already participated in six studies, and she meets every month or two to help train medical students at Rutgers University. She also enjoys volunteering with a youth group at her synagogue that’s engaged in community service. Giving back “is part of our values as a family,” says Ann. “Yes, Mora’s got all these issues. Those are the lemons. This is the lemonade: She has something to contribute, and it’s meaningful.”

For Mora, while the future is uncertain, she says she'd like to become an accountant, and her parents hope she can work toward an independent life. Mora sounds ready for the challenge. “I call myself ‘the glass half-full girl,’ because I am optimistic about myself,” she says. “I think things are going to be good, and I am going to be happy.”

For more on Mora Leeb, pick up the latest issue of PEOPLE, available on newsstands this Friday.

Courtesy of my daughter

Cannabidiol-associated hepatotoxicity

Courtesy of a colleague

Lo LA, Christiansen A, Eadie L, Strickland JC, Kim DD, Boivin M, Barr AM, MacCallum CA. Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis. J Intern Med. 2023 Jun;293(6):724-752. doi: 10.1111/joim.13627. Epub 2023 Mar 13. PMID: 36912195.


Background: Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI).

Methods: In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL,, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted.

Results: Cannabidiol use was associated with an increased probability of liver enzyme elevation (N = 12 trials, n = 1229; OR = 5.85 95% CI = 3.84-8.92, p < 0.001) and DILI (N = 12 trials, n = 1229; OR = 4.82 95% CI = 2.46-9.45, p < 0.001) compared to placebo controls. In participants taking cannabidiol (N = 28 trials, n = 1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000 mg/day or ≥20 mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300 mg/day. No cases of severe DILI were reported.

Conclusions: Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.

I had whole exome sequencing performed again.

My initial round of whole exome sequencing in 2018 couldn't have been normaller. I have a slowly progressive peripheral neuropathy. In 2022, through the efforts of the Unidentified Diseases Network, I had a repeat whole exome sequencing performed through the Baylor laboratory. I was found to have 2 missense mutations in TTN:: c.70712 C>A p.Ala23571Asp & c.28733C>T p.Thr9578Met, consistent with SORD hereditary neuropathy. As anticipated, my urine sorbitol was strikingly elevated.


Thursday, November 30, 2023

Chopsticks hazard

A pounding headache led to a shocking discovery for a man in Vietnam, after the source of the pain was revealed to be a pair of chopsticks.

After the man experienced severe headaches for five months, doctors at Cuba Friendship Hospital in Dong Hoi told the 35-year-old man that he had a pair of chopsticks lodged inside his skull, according to the New York Post.

Upon checking into the hospital on Nov. 25, a CT scan revealed that the man was suffering from a rare, potentially life-threatening neurological condition that was caused by the pair of chopsticks that had allegedly gone up his nose and into his brain.

The Post reported that while the man was initially surprised at how chopsticks ended up inside his skull, he soon remembered a fight he was involved in while out drinking five months prior.

The patient reportedly told doctors that he could not recall many details from the fight, but did remember someone stabbing him in the face with an unknown object.

The surgeons were able to successfully remove the chopsticks and the patient was said to be in stable condition, waiting to be released from the hospital.

After conducting CT scans, it was discovered that the man was suffering from tension pneumocephalus. This rare neurological condition is characterized by a hazardous elevation in intracranial pressure. Subsequent examinations unveiled the unusual cause of the man's symptoms: a pair of chopsticks that had reportedly entered through his nose and reached his brain.

Initially perplexed by the presence of chopsticks in his brain, the man recollected that he had been involved in a fight five months earlier while drinking in Vietnam, as reported by Vietnam. VN. The details of the fight were hazy in his memory, but he vaguely remembered being stabbed in the face with an unknown object.

Doctors were able to successfully remove the chopsticks.

A man in Vietnam who experienced severe headaches for about five months was shocked after discovering that he had a pair of chopsticks lodged in his brain. The 35-year-old patient sought medical attention at Dong Hoi's Cuba Friendship Hospital on November 25. He complained of severe headaches, along with fluid discharge and loss, the New York Post reported.

After conducting CT scans, it was discovered that the man was suffering from tension pneumocephalus. This rare neurological condition is characterized by a hazardous elevation in intracranial pressure. Subsequent examinations unveiled the unusual cause of the man's symptoms: a pair of chopsticks that had reportedly entered through his nose and reached his brain.

Initially perplexed by the presence of chopsticks in his brain, the man recollected that he had been involved in a fight five months earlier while drinking in Vietnam, as reported by Vietnam. VN. The details of the fight were hazy in his memory, but he vaguely remembered being stabbed in the face with an unknown object.

Despite reporting to the hospital after the incident, doctors at the time found no chopsticks or abnormalities in his nose. In hindsight, the bewildered patient now speculates that he was stabbed in the nose with the food forceps during the fight, and they remained undiscovered in his skull until recently.

Fortunately, through endoscopic surgery performed through the nose, doctors were able to successfully remove the chopsticks.

Following that, microsurgery was employed to close the fistula, an abnormal connection between the artery and vein in the brain and spinal cord tissue.

The patient is said to be in stable condition as he awaits discharge from the hospital.

Drug reaction with eosinophilia and system syndromes (DRESS) with levetiracetam and clobazam

The Food and Drug Administration (FDA) has issued an alert that the antisezure medications levetiracetam and clobazam may cause a rare but serious reaction, which can be life-threatening if left undiagnosed and untreated. The reaction, which may begin with a rash before progressing to injury of the internal organs and potentially death, is called Drug Reaction with Eosinophilia and System Syndromes (DRESS). DRESS can cause symptoms including fever, rash, swelling of the lymph nodes, and injury to the liver, kidneys, lungs, heart, or pancreas.

Levetiracetam is available under multiple brand names, including Keppra (levetiracetam; UCB, Atlanta, GA) and Spritam (levetiracetam; Aprecia Pharmaceuticals, Langhorne, PA), while clobazam is marketed as Onfi (clobazam; Lundbeck, Deerfield, IL) and Sympazan (clobazam; Aquestive Therapeutics, Warren, NJ). The FDA will require manufacturers of these medications and other formulations of levetiracetam and clobazam to add a new warning to the Warnings & Precautions sections of their prescribing information, which will describe the serious and significant safety issues related to DRESS. Manufacturers will also be required to add warnings to the medication guides for levetiracetam and clobazam, informing patients and caregivers about the early symptoms of the reaction and its potential risks.

In the alert, the FDA states that health care professionals should be aware of the following:
Recognizing and treating DRESS early is essential for improving outcomes and decreasing mortality.
Symptoms and intensity can vary, with DRESS typically developing 2 to 8 weeks after treatment initiation.
DRESS symptoms, such as fever and swollen lymph nodes, may be present without rash, and symptoms may be difficult to distinguish from other serious skin reactions. 

Adverse events or side effects related to these medications should be reported to the FDA.

Tuesday, November 28, 2023

Functional insights into the pathology of migraine subtypes, with and without aura

Bjornsdottir G, Chalmer MA, Stefansdottir L, Skuladottir AT, Einarsson G, Andresdottir M, Beyter D, Ferkingstad E, Gretarsdottir S, Halldorsson BV, Halldorsson GH, Helgadottir A, Helgason H, Hjorleifsson Eldjarn G, Jonasdottir A, Jonasdottir A, Jonsdottir I, Knowlton KU, Nadauld LD, Lund SH, Magnusson OT, Melsted P, Moore KHS, Oddsson A, Olason PI, Sigurdsson A, Stefansson OA, Saemundsdottir J, Sveinbjornsson G, Tragante V, Unnsteinsdottir U, Walters GB, Zink F, Rødevand L, Andreassen OA, Igland J, Lie RT, Haavik J, Banasik K, Brunak S, Didriksen M, T Bruun M, Erikstrup C, Kogelman LJA, Nielsen KR, Sørensen E, Pedersen OB, Ullum H; DBDS Genetic Consortium; Masson G, Thorsteinsdottir U, Olesen J, Ludvigsson P, Thorarensen O, Bjornsdottir A, Sigurdardottir GR, Sveinsson OA, Ostrowski SR, Holm H, Gudbjartsson DF, Thorleifsson G, Sulem P, Stefansson H, Thorgeirsson TE, Hansen TF, Stefansson K. Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura. Nat Genet. 2023 Nov;55(11):1843-1853. doi: 10.1038/s41588-023-01538-0. Epub 2023 Oct 26. PMID: 37884687; PMCID: PMC10632135.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.


An analysis of genetic data from more than 1.3 million people has revealed new biological pathways associated with migraine that could potentially be targeted for drug development. Researchers published their findings in Nature Genetics.

“Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes,” wrote corresponding author Gyda Bjornsdottir, PhD, of deCODE Genetics, a subsidiary of Amgen Inc. based in Reykjavik, Iceland, and study coauthors.

The analysis combined large genome-wide association study (GWAS) datasets from 6 European populations in an attempt to detect sequence variants associated with the two main subtypes of migraine: migraine with aura and migraine without aura. Among participants sequenced, 17,000 had migraine with aura, 12,000 had migraine without aura, and 80,000 had any migraine.

Migraine was associated with 44 variants, according to the study. Twelve of the associations were novel, while 4 new associations were identified for migraine with aura (in PRRT2, PALMD, ABO, and LRRK2), and 13 variants were classified for migraine without aura.

The research team reported rare variants with large effects highlighting 3 genes. First, a rare frameshift variant in the PRRT2 gene conferred a large risk of migraine with aura and epilepsy, but not migraine without aura. Second, a burden test of rare loss-of-function variants in the SCN11A gene, which plays a key role in pain sensation, showed strong protection against migraine. Meanwhile, a common missense variant in SCN11A was associated with modest migraine risk.

Third, a rare variant pointing to the KCNK5 gene conferred large protection against migraine and brain aneurysms. The finding either identifies a common pathway between the two diseases or suggests that some cases of undetected brain aneurysms may be misclassified as migraine, the team explained.

“In all, our findings are consistent with the results of previous GWAS analyses that have established migraine as a complex neurovascular brain disorder,” researchers wrote. “However, our results also highlight several distinct biological pathways involved in migraine with aura and migraine without aura that warrant further study.”

Sunday, November 19, 2023

Munchausen by proxy 2

Maya Kowalski, the 17-year-old who was awarded more than $260 million in damages and punitive damages in her civil lawsuit against a Florida children's hospital, has filed a sexual assault complaint against the hospital, according to her attorney. 

Maya; her father, Jack Kowalski; and her brother, Kyle Kowalski, accused staff at Johns Hopkins All Children's Hospital (JHAC) in St. Petersburg of falsely imprisoning Maya, fraudulently billing their family and causing their family severe emotional distress. They said the hospital's actions, including making medical abuse allegations against Maya's mother, Beata Kowalski, drove Beata to suicide in 2017.

The case took the country by storm after it inspired the popular documentary series "Take Care of Maya," which follows the story of Maya and Beata as they navigated Maya's rare, chronic neurological condition called complex regional pain syndrome (CRPS) – an obscure condition that causes severe pain throughout a person's body due to nervous system dysfunction, according to the Cleveland Clinic.

"I am claiming that there was sexual abuse. It's something that I was quite quiet about for a couple of years because I was worried it wasn't going to be taken seriously," Maya told Fox News' Martha MacCallum on Thursday.

Ethen Shapiro, an attorney from Hill Ward Henderson who represented JHAC in the case, told Fox News Digital in a statement that Maya's "allegations originally arose during trial and were not admitted into the case."

"As soon as the hospital became aware of the allegations, and in accordance with their policies, they immediately initiated an internal investigation and contacted law enforcement last month," Shapiro said. "Federal privacy laws restrict Johns Hopkins All Children’s Hospital from sharing more, but the hospital takes allegations of this nature very seriously and always puts the safety of their patients above all else."

In 2016, Maya was admitted to JHAC for severe pain caused by her CRPS, which was previously diagnosed by another Florida doctor. 

Later that year, a court order removed Maya from the custody of her parents after staff accused Beata of medical abuse, saying that she exhibited signs of Munchausen by proxy, in part because Beata was insisting to JHAC that Maya needed heavy doses of ketamine to ease her pain. 

"It's absolutely preposterous that someone would say that my mother was forcing these symptoms onto me. You have to remember – her and I both – we didn't know what I had. No one did. So, she couldn't come up with a list of symptoms and make up this disease," Maya said Thursday.

Beata hanged herself in her garage in January 2017 after being separated from her hospitalized daughter for months. 

"I know that my mom gave up her life for me. I understood that at the age of 11 years old," Maya continued. "Now, I try to go on. I try to live my life as positively as I can, but I want people to know that in her doing that, she wasn't giving up. As a matter of fact, in her doing that, that’s the only way she saw for us to win."

Her attorney, Greg Anderson, noted that JHAC continued to bill the Kowalski family for CRPS even after saying Maya did not have the condition and accusing her mother of making up Maya's symptoms for her. 

"There were medical records within Johns Hopkins where they had seen her 17 times," Anderson told MacCallum. "This was not her first visit there, and since the diagnosis by Dr. Kirkpatrick at the RSD institute, everyone had adopted that CRPS, but on this one evening, a team of ER doctors decided for whatever reason that they would go against five different experts and decide that it didn't meet their own internal protocols… and change everything."

Multiple witnesses, including health care professionals at JHAC, testified during the trial that Beata had been exhibiting signs of Munchausen by proxy and that Maya's perceived CRPS symptoms had been driven by her mother. Munchausen by proxy is a psychological disorder in which an abusive parent or caretaker makes up or causes an illness for a person under their care – often the parent's own child – who is not actually ill. 

The defense argued over the course of the trial that hospitals have a responsibility to report abuse when they see it, and in Maya's case, doctors agreed that Beata was exhibiting abusive behavior, including what they described as unsafe doses of ketamine Beata gave her daughter.

"One of the most unfortunate parts of this case is the caption: Kowalskis v. All Children's. We were never against the Kowalski family," attorney Ethen Shapiro, who represented JHAC, said in his closing statements. "The reason why All Children's did what it did, the reason why All Children's tried to comfort Maya, the reason why All Children's tried to get her on a safe medical path is because the loving and caring providers at my clients' hospital believed in a better future for her if they could get her off the unnecessary drugs given at dangerous levels."

Howard Hunter, an attorney with Hill Ward Henderson who representing JHAC in this case, thanked the jury for their "time and attention" in a statement to Fox News Digital. He added that JHAC plans to appeal the decision "based on clear and prejudicial errors throughout the trial and deliberate conduct by plaintiff’s counsel that misled the jury."

"The evidence clearly showed that [JHAC] followed Florida’s mandatory reporting law in reporting suspected child abuse and, when those suspicions were confirmed by the district court, fully complied with Department of Children and Families (DCF) and court orders," Hunter said.

"We are determined to defend the vitally important obligation of mandatory reporters to report suspected child abuse and protect the smallest and most vulnerable among us. The facts and the law remain on our side, and we will continue to defend the lifesaving and compassionate care provided to Maya Kowalski by the physicians, nurses and staff of Johns Hopkins All Children’s Hospital and the responsibility of all mandatory reporters in Florida to speak up if they suspect child abuse."

Wednesday, November 15, 2023

MECP2 duplication syndrome

Inspired by a patient

Kim TY, Lee SJ, Kim KM, Cho SR. MECP2 duplication syndrome initially misdiagnosed as cerebral palsy: a case report. J Int Med Res. 2023 Mar;51(3):3000605231162452. doi: 10.1177/03000605231162452. PMID: 36988314; PMCID: PMC10064467.


Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene were first described as a cause of Rett syndrome. MECP2 duplication can cause intellectual disability, developmental delay, severe feeding difficulties, and recurrent infections. Here, we report a Korean family with MECP2 duplication syndrome, which was previously misdiagnosed as cerebral palsy. A man in his early 30 s visited our clinic with intellectual disability, speech impairment, epilepsy, and progressive spasticity. He had been previously misdiagnosed with cerebral palsy, and had received orthopedic surgeries such as musculotendinous lengthening and derotational osteotomy. After the surgeries, he received comprehensive rehabilitation. Upon carefully checking his family history, we noted that his younger brother had similar symptoms. Next-generation sequencing revealed whole exon duplication in MECP2 in both the patient and his brother; their mother also had this genetic mutation but was asymptomatic. Early diagnosis is essential for improving the success of MECP2 duplication syndrome treatment. Individuals with MECP2 duplication syndrome should be referred to specialists to manage multidisciplinary symptoms and to regularly check for complications that are common in this syndrome.

Ak M, Suter B, Akturk Z, Harris H, Bowyer K, Mignon L, Pasupuleti S, Glaze DG, Pehlivan D. Exploring the characteristics and most bothersome symptoms in MECP2 duplication syndrome to pave the path toward developing parent-oriented outcome measures. Mol Genet Genomic Med. 2022 Aug;10(8):e1989. doi: 10.1002/mgg3.1989. Epub 2022 Jun 15. PMID: 35702943; PMCID: PMC9356562.


Background: MECP2 Duplication Syndrome (MDS), resulting from the duplication of Xq28 region, including MECP2, is a rare disorder with a nascent understanding in clinical features and severity. Studies using antisense oligonucleotides revealed a broad phenotypic rescue in transgenic mice. With human clinical trials on the horizon, there is a need to develop clinical outcome measures for MDS.

Methods: We surveyed caregivers of MDS individuals to explore the frequency and severity of MDS clinical features, and identify the most meaningful symptoms/domains that need to be included in the outcome measure scales.

Results: A total of 101 responses were eligible for the survey. The top six most meaningful symptoms to caregivers in descending order included epilepsy, gross motor, fine motor, communication, infection, and constipation problems. Epilepsy was present in 58.4% of the subjects and 75% were drug-resistant, Furthermore, ~12% required intensive care unit (ICU) admission. Infections were present in 55% of the subjects, and one-fourth of them required ICU admission. Constipation was present in ~85% of the subjects and one-third required enemas/suppositories.

Conclusion: Our study is one of the largest cohorts conducted on MDS individuals characterizing the frequency and severity of MDS symptoms. Additionally, these study results will contribute to establishing a foundation to develop parent-reported outcomes in MDS.

John Cherian D, Ta D, Smith J, Downs J, Leonard H. How Families Manage the Complex Medical Needs of Their Children with MECP2 Duplication Syndrome. Children (Basel). 2023 Jul 11;10(7):1202. doi: 10.3390/children10071202. PMID: 37508699; PMCID: PMC10377896.


MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder resulting from the duplication of the methyl-CpG-binding protein 2 (MECP2) gene. The clinical features of MDS include severe intellectual disability, global developmental delay, seizures, recurrent respiratory infections, and gastrointestinal problems. The aim of this qualitative study was to explore how the parents of children with MDS manage their child's seizures, recurrent respiratory infections, and gastrointestinal symptoms, and the impact on them as parents. The data were coded into three categories: (1) complex care needs in the home, (2) highly skilled caregivers, and (3) impact on caregivers and families. Complex 24 h care was required and parents developed complex skillsets to ensure that this was delivered well to their child. The provision of extensive complex medical care in the home had an impact on parent mental and physical health, family dynamics, and finances. This study captures the management of high-burden comorbidities in MDS at home. Investigations into how best to support caregiver wellbeing to reduce their stresses, whilst maintaining optimal child health and wellbeing, are needed.

Ak M, Akturk Z, Bowyer K, Mignon L, Pasupuleti S, Glaze DG, Suter B, Pehlivan D. Assessing the Burden on Caregivers of MECP2 Duplication Syndrome. Pediatr Neurol. 2022 Aug;133:1-8. doi: 10.1016/j.pediatrneurol.2022.05.008. Epub 2022 May 25. PMID: 35716604.


Background: MECP2 duplication syndrome (MDS) is a rare neurogenetic disorder characterized by severe neurodevelopmental disorder, refractory epilepsy, recurrent infections, and functional gastrointestinal problems. Because of the significant clinical problems and lifelong disability of children with this disorder we hypothesized that the burden on parents/caregivers of these children is significant. However, there are no reports of the impact on caregivers of individuals with MDS.

Methods: We developed and validated a burden scale to investigate the challenges of caregivers of children and adults with MDS and identified factors contributing to the burden on caregivers. We developed a Health Insurance Portability and Accountability Act-compliant patient registry for families with MDS and delivered caregiver burden survey through the registry.

Results: Of 237 completed surveys, 101 were eligible for the study. We identified increased levels of self-perceived anxiety, depression, and emotional exhaustion in caregivers that correlated with higher burden scores. Epilepsy was the only clinical feature that caused a higher burden in caregivers of individuals with MDS. In addition, a higher burden was found in Hispanic caregivers. The duration of care negatively correlated with burden score.

Conclusions: This is the first study to investigate the burden on caregivers of individuals with MDS and identify several factors contributing to increased burden. Addressing these concerns has the potential to improve the health of individuals with MDS and contribute to the well-being of their caretakers.

Friday, November 10, 2023

Death at the order of the United Kingdom court

An 8-month-old infant in the United Kingdom has been given more time to live after an appeal suspended a judge's mandate that she be removed from life support.

Justice Robert Peel ruled Wednesday that Indi Gregory was to be removed from her life-supporting ventilator on Thursday against the parents' wishes.

Now, the Gregory family has successfully launched an appeal to that mandate, hoping to negotiate the right to seek continued treatment overseas.

Indi Gregory was born in February of this year and suffers from a degenerative mitochondrial disease that will very likely take her life.

In a bid to escape the mandate to remove life support, the Gregorys made emergency arrangements with leadership at the Vatican for her to continue treatment at Bambino Gesù, a Catholic pediatric hospital in Rome.

The parents also secured Italian citizenship for Indi directly from the Italian prime minister.

"They say there isn’t much hope for little Indi, but until the very end, I’ll do what I can to defend her life, and to defend the right of her mamma and papa to do all that they can for her," Italian Prime Minister Giorgia Meloni wrote on social media this week.

The Court of Appeals will hear the Gregorys' case on Nov. 10. 

Doctors at Queen's Medical Center in Nottingham will not be allowed to remove the infant from life support until the conclusion of the appeals process.

The Italian government has pressed the U.K. courts heavily to turn the child over to their custody.

"Earlier today, with the clock ticking, Indi's Italian guardian made an urgent application to the U.K. High Court calling on Mr Justice Robert Peel to cede jurisdiction of the case to him under Article 9§2 of the 1996 Hague Convention," religious legal group Christian Concern explained Friday.

Christian Concern hopes that the increasingly international nature of the case will force the courts to back down, claiming that "such a development has never happened before in an end-of-life case involving a child in the U.K."

Tuesday, November 7, 2023

Elemental dynamics in hair accurately predict future autism spectrum disorder diagnosis

Mirabile dictu

Austin C, Curtin P, Arora M, Reichenberg A, Curtin A, Iwai-Shimada M, Wright RO, Wright RJ, Remnelius KL, Isaksson J, Bölte S, Nakayama SF. Elemental Dynamics in Hair Accurately Predict Future Autism Spectrum Disorder Diagnosis: An International Multi-Center Study. J Clin Med. 2022 Dec 1;11(23):7154. doi: 10.3390/jcm11237154. PMID: 36498727; PMCID: PMC9740182.


Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.

Friday, November 3, 2023

Munchausen by proxy

Lawyers defending Johns Hopkins All Children's Hospital (JHAC) in a $220 million medical malpractice lawsuit waged by Maya Kowalski and her family showed jurors photos of the teenager smiling at prom, homecoming and for Halloween.

The 17-year-old, whose story was the subject of the Netflix documentary "Take Care of Maya," is suing the Florida hospital after a saga that led to her mother Beata Kowalski's suicide following accusations of Munchausen syndrome by proxy.

Maya's attorney Gregory Anderson told Court TV on Oct. 27 that the symptoms of his client's complex regional pain syndrome (CRPS) — a poorly understood neuropathic condition — have worsened amid the stressors of the ongoing trial. 

Due to her "flare-up," the teen was unable to attend court hearings for several days, Anderson said. But attorneys for JHAC showed photos of Maya posing in dresses, heels and even a skimpy angel Halloween costume on Tuesday, saying the snaps of the teen out on the town contradicted those claims. 

For nearly six weeks, jurors have heard testimony from experts and Maya's doctors and nurses at the Florida hospital.

JHAC called the child abuse hotline after Beata, a registered nurse, insisted that the then-10-year-old Maya needed what the hospital claimed was a dangerously high amount of ketamine to treat a flare-up of her chronic pain in 2016.

Previously, the family told hospital staff, the girl had undergone an experimental ketamine coma in Mexico that has not been approved for treatment in the U.S. 

Staff reported Beata for medical child abuse, leading a judge to order Maya's separation from her family in 2016 for more than 80 days. JHAC's attorney Ethen Shapiro told reporters recently that the hospital's intervention is what "[got Maya to] where we see her today — walking in and out of court, going to homecoming, living a more normal teenage life." 

"A lot of the world is watching. This is potentially a very chilling case for mandatory reporting," Shapiro said in an audio clip provided to Fox News Digital. "Hopefully by mandatory reporters seeing that we're sticking up for them... [and it] will help affirm their duties." 

But Maya and her family allege that reporting Beata for Munchausen syndrome by proxy and forcibly separating the family amounted to false imprisonment, medical malpractice and infliction of emotional distress — and led Beata to hang herself in the family's garage in January 2017.

A doctor who had previously prescribed Maya's ketamine treatments told the court that his prescribed regimen was medically sound — but, in opposition, emeritus professor of anesthesiology and chief of pain management at the Stanford School of Medicine Dr. Elliot Krane told the court this week that the experimental treatment was dangerous and illegal in the U.S. 

In previous court hearings, JHAC's attorney Howard Hunter said JHAC believed Maya was "given levels of medication they had never heard of before, that the literature did not support," per earlier reporting by Fox News Digital.

Staff made the call fearing that Maya's mother suffered from Munchausen by proxy and was making her daughter sick, Hunter has argued. 

In court, the teen has said that the ketamine treatment improved symptoms that would leave her screaming in pain. 

"This is the life of Maya Kowalski today," Shapiro told the court. "We did not aggravate a pre-existing condition. She's at her prom, she's out in heels, has friends — it's in complete contradiction to her testimony. 

Several of the social media photos were admitted into evidence despite protests from Maya's attorneys. 

Before resting its case, the defense showed video depositions from Maya, her father Jack Kowalski and her uncle Scott Kowalski. 

Maya said in her deposition that her symptoms have receded – she currently only takes Claritin for allergies and a sleeping pill, she said, and enjoys running, swimming and ice skating. 

Jack testified that he no longer sees signs of his daughter's alleged CRPS.

But in her rebuttal, Maya told the court that her smiling photos at prom and other events are not proof that she is no longer in pain, and that she often masks her symptoms. 

"I cried for an hour to my dad before that picture was taken because of how bad my leg pain was," she told jurors on Tuesday. "I wasn't sure if I was going to be able to go. That was my physical condition and mental condition." 

The teen explained that she didn't want to disappoint her boyfriend, who had already purchased tickets for the homecoming dance where she was pictured. 

"I did not post that picture, meaning the defense went as far as to look up my friends' account," she continued.

Maya testified that her pain level was at a "seven or eight" that day, per courtroom footage. Her current symptoms, she said, include lesions and discolorations in her right leg. She currently experiences involuntary jerking in her body, she said — those jerking motions started "after Johns Hopkins Children's Hospital," she said Tuesday.

Shapiro said after court Tuesday, per a recording shared with Fox News Digital, that he was "very confident" after his closing arguments. 

Staff at JHAC suspected that Beata Kowalski was suffering Munchausen syndrome by proxy after she pushed for unapproved ketamine treatment for her daughter's condition. (WTVT)

JHAC previously told Fox News Digital in a statement that the hospital's priority is "always the safety and privacy" of its "patients and their families."

Tuesday, October 24, 2023

Vinpocetine for GABR mutations

Mandelenaki D, Juvené E, Gederer D, Aeby A. Precision medicine: Vinpocetine as a potential treatment for GABRG2-related epilepsy. Epileptic Disord. 2023 Jun;25(3):383-389. doi:10.1002/epd2.20015. Epub 2023 May 25. PMID: 37536979.


Introduction: Pathogenic variants of the GABRG2 gene, encoding a GABAA receptor subunit, have been associated with various epileptic syndromes and drug-resistant epilepsy. Vinpocetine has been previously reported efficacious in a patient harboring a GABRB3 pathogenic variant, encoding another GABAA receptor subunit.

Case presentation: We describe a patient with GABRG2-related drug-resistant epilepsy who improved after vinpocetine treatment. An 8-year-old boy with a family history of epilepsy was diagnosed with early onset absence epilepsy at 6 months of age and was treated unsuccessfully with sodium valproate and ethosuximide. At 6 years of age, he developed generalized tonic-clonic seizures and increasing absences despite lamotrigine add-on as well as learning difficulties. Brain MRI was normal and video-EEG telemetry showed multiple myoclonic absences. An epilepsy gene panel analysis showed a GABRG2 pathogenic variant, c.254 T > A p.(Ile85Lys) (NM_198903.2), inherited from the proband's father. Seizures were resistant to several medications. After treatment with vinpocetine add-on, the patient showed a dramatic initial response, further reduction of seizures, and improvement of his cognitive functions.

Conclusion: This case illustrates that vinpocetine could be considered in drug-resistant epilepsies related to GABRG2 in accordance with the principles of precision medicine.

Billakota S, Andresen JM, Gay BC, Stewart GR, Fedorov NB, Gerlach AC, Devinsky O. Personalized medicine: Vinpocetine to reverse effects of GABRB3 mutation. Epilepsia. 2019 Dec;60(12):2459-2465. doi: 10.1111/epi.16394. Epub 2019 Nov 22. PMID: 31755996; PMCID: PMC7004153.


Objective: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation.

Methods: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation.

Results: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention.

Significance: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.

Gjerulfsen CE, Mieszczanek TS, Johannesen KM, Liao VWY, Chebib M, Nørby HAJ, Gardella E, Rubboli G, Ahring P, Møller RS. Vinpocetine improved neuropsychiatric and epileptic outcomes in a patient with a GABRA1 loss-of-function variant. Ann Clin Transl Neurol. 2023 Aug;10(8):1493-1498. doi: 10.1002/acn3.51838. Epub 2023 Jul 11. PMID: 37434477; PMCID: PMC10424645.


Vinpocetine is a synthetic derivative of the alkaloid vincamine and has been used as a dietary supplement for decades. Following a positive report of the use of vinpocetine in a patient with a loss-of-function GABRB3 variant, we here describe another patient with a loss-of-function GABRA1 variant (p.(Arg112Gln)) who benefited from vinpocetine treatment. This patient was diagnosed with autism spectrum disorder, psychiatric complications, and therapy-resistant focal epilepsy. Upon add-on treatment with 40 mg vinpocetine daily for 16 months, the patient experienced an overall improved quality of life as well as seizure freedom. Our findings corroborate that vinpocetine can attenuate epilepsy-associated behavioral issues in patients with loss-of-function GABAA receptor gene variants.

Monday, October 16, 2023

Febrile seizures

 In a matter of seconds, Kelly Herrmann’s son Howie went from sleeping in her arms to having a seizure.

She recognized he was having a seizure but didn’t know why.

“I was holding him, and he started to turn blue and stopped breathing. I honestly thought he was dying in my arms,” she said.

Earlier in the day, Howie’s day care called Herrmann and said he had a fever. Little did Herrmann or her husband Seth Moser know, a fever in children sometimes causes what’s known as a febrile seizure.

Febrile seizure, explained

Mohamad Saifeddine, M.D., is a pediatric neurology specialist at Sanford Health in Sioux Falls, South Dakota. He said sometimes a febrile seizure can be caused from a brain infection but oftentimes, like in Howie’s case, it’s caused from a fever.

“A febrile seizure is a seizure that happens in the setting of fever. That means the seizure itself is abnormal firing of electricity in the brain, that spreads throughout the brain and causes the child to have different movements and being unconscious,” he said.

How common are febrile seizures?

Dr. Saifeddine said it’s actually a very common condition in children, particularly in children between the ages of one and a half years old to three years of age.

“Statistically, it’s up to 2-5% of kids actually going to have at least one febrile seizure in their lifetime,” he said.

These types of seizures typically last one to two minutes, but “it can be shorter and unfortunately it can be longer,” Dr. Saifeddine explained.

Related: Stroke or seizure? It can be a fine line between the two

If a seizure lasts longer than three to five minutes, it’s called a “status.” Meaning, the prolonged seizure is not stopping by itself.

“That’s when we need to ask or seek medical help for any parents. That’s when parents should come to the ER or call 911,” he said.

What if my child is having a febrile seizure?

According to Dr. Saifeddine, the most important thing a parent can do when their child is having a seizure, whether it’s febrile or not, “is to put the child on their side.”

“Do not put anything in their mouth, and make sure that the child doesn’t have something sharp or hard under their head, so if the child is actually seizing, meaning they’re having whole-body jerking, they won’t hit their head with something that can injure themself,” he said.

He said it can be an extremely difficult thing to remember to do, but he recommends someone checks the time while the child is having the seizure.

“If the seizure is more than two or three minutes and the child is not waking up, somebody (then) has to call 911.”

‘It was confusing and also a relief’

When Howie was having his febrile seizure, Hermann rushed over to her neighbors, Howie still blue in her arms, and asked them to call 911.

Thankfully, when the ambulance arrived, Howie’s febrile seizure had stopped. The EMT explained to Herrmann that Howie most likely had a febrile seizure, and that it was very common.

Seek care: Well child visits important for children of all ages

Herrmann, having never heard of a febrile seizure or that it’s often caused by a fever, had questions swirling.

“If it was so common, how did I not know what that was? His fever was so low. It 100.4, and even in the ambulance, it was still only 100.5 or so. So, in my mind it just didn’t make sense, because yes, he had a fever, but just barely. It wasn’t anything too high,” Hermann said.

“So, it was like a relief, but also I was still confused. I was still worried that something was wrong. I was worried he was going to have another one. Despite learning more from the care team, it was still really confusing and scary,” she added.

Howie is home and doing just fine, a relief to is entire family.

Herrmann said her take home message for parents is to know febrile seizures exist and be prepared if their child has one.

“Don’t put anything in their mouth, and try to keep the airway open. Pay attention to how long it’s lasting, because if it lasts a really long time, that can be a problem.”

Friday, September 22, 2023

Melatonin concerns

As a growing number of American parents are giving their kids melatonin to help them fall asleep, some experts are warning of potential risks.

Nearly half (46%) of parents in the U.S. have given melatonin to a child under the age of 13, and almost one-third (30%) of parents have given the supplement to a teen over the age of 13 to help him or her fall asleep, according to a recent survey from the American Academy of Sleep Medicine (AASM).

Providing melatonin to children might seem like a natural solution — but a 2022 AASM health advisory warns against using it for children because melatonin is not regulated by the federal Food and Drug Administration (FDA).

The rise in melatonin use has also led to a spike in reports of melatonin overdose, calls to poison control centers and emergency room visits among children, the AASM has stated.

Dr. Anne Marie Morse, a pediatric neurologist in Danville, Pennsylvania, was not surprised to hear about the high prevalence of melatonin use among kids.

"We've seen that in pediatrics, it is much more likely for there to be a prescription to help a child sleep as opposed to adults," she said in an interview with Fox News Digital.

"So, it doesn't surprise me that even before a prescription is given, a parent is asking, ‘What can I do myself? What can I get my hands on to be able to help my child sleep?’"

"Because when your child's not sleeping, the whole house isn't sleeping and it can be extraordinarily disruptive," she added.

Overall, Morse sees melatonin as relatively safe. But she emphasized the need to talk with a doctor before doling it out.

"If you're going to give your child any supplements, you should really have a conversation with your physician first, to make sure it’s the right solution for the problem you’re experiencing," she said. "The doctor can also discuss dosing and how long to utilize it."

As a sleep physician who sees kids and adults, Morse said she "commonly" utilizes melatonin, especially for teenagers who have a delayed sleep phase, meaning that their circadian rhythm has shifted much later than what it should be.

"Melatonin can be very helpful in shifting the circadian rhythm," she said.

When using it for that purpose, Morse usually recommends much lower doses — sometimes as low as 0.3 to 0.5 mg — and using it further away from bedtime.

When using melatonin just for the purpose of helping someone fall asleep, she said she may recommend higher dosing — anywhere between 1 and 10 mg — and recommend taking it closer to bedtime.

As far as how long melatonin is used, Morse said it depends on the patients.

"Research has demonstrated that some populations, such as individuals with autism spectrum disorder, require longer-term treatment with melatonin," she said.

One of the biggest concerns is that melatonin is a hormone produced by the brain, Morse noted, and could potentially influence other hormones the body produces.

"In 2022, there was a 600% increase in poison control calls related to taking too much melatonin."

In animal studies, melatonin has been shown to affect the sex hormones, which can influence the timing of puberty, she warned.

"That's why we tend to be cautious about long-term use if it's not necessary," she said.

Morse’s typical approach is to start the medication, identify whether there's a benefit within three months, then take away the melatonin and gauge whether the benefit is still there.

"The goal is to partner any medication with behavioral strategies that make the medication less necessary for long-term use," she said.

Lack of regulation

Another potential concern, Morse noted, is that there is a "high degree of variability" in how much melatonin may be in any given product.

In a recent study from earlier this year, it was found that there could be anywhere from half of what was being stated on the bottle to as much as four times the amount, she said.

"The challenge is that because it's not a regulated substance in the U.S., there is a lack of predictability," she said.

To reduce the risk, Morse recommended starting with the lowest available dose.

"That way, you know the child won’t get too high of a dose, because there really is no way to predict how much the bottle is going to have."

A study in April by the Cambridge Health Alliance revealed that some melatonin gummies — which can be more appealing to kids — contained amounts far in excess of what the label indicated.

"If consumers decide to try melatonin — particularly if giving it to children — they should seek out a product that is certified by either USP (United States Pharmacopeia) or NSF (formerly the National Sanitation Foundation, now NSF International), as that is the only way to be certain that the product is accurately labeled," study author Dr. Pieter Cohen, associate professor of medicine at Harvard Medical School in Somerville, Massachusetts, told Fox News Digital at the time.

"It’s hard to say whether the short-term benefits outweigh the possible risks."

Although melatonin is a natural hormone, it is possible for people to have adverse effects from taking too much, Morse confirmed.

"In 2022, there was a 600% increase in poison control calls related to taking too much melatonin," the doctor said.

"Thankfully, there hasn’t been any evidence that it can cause something like respiratory depression, coma or death — but it can cause adverse effects like oversedation, nausea and grogginess the next day," she noted.

One study has suggested that melatonin in high doses and for prolonged periods of time could potentially increase the risk of seizures, Morse said, but "that has not been replicated."

While melatonin has a role in improving sleep, the doctor noted that it doesn’t treat all types of sleep disorders.

"Just like any medical disorder, it is important to make sure that you're identifying and treating the right one," she said. "Make sure to talk with your physician and see a sleep doctor if necessary, to make sure you're getting the appropriate treatment."

Dr. Laura Purdy, a board-certified family medicine physician in Miami, Florida, reiterated that the long-term effects of melatonin on kids aren’t known, as there isn’t yet enough research.

"I would use caution on things we don’t know more about long-term," she told Fox News Digital. "It’s hard to say whether the short-term benefits outweigh the possible risks."

Potential short-term risks include increased bedwetting, agitation and mood swings, fatigue and drowsiness, stomach pains and nausea, Purdy warned.

"Just like any medical disorder, it is important to make sure that you're identifying and treating the right one."

"Long-term risks that are being looked into more include worries about negative impacts on your child’s growth and development," she added.

"There are other ways to help your child fall asleep that I suggest trying first," she said. "If you have any questions or concerns, consult your doctor."

Importance of good ‘sleep hygiene’

As far as how much sleep kids need, Morse said it varies by age.

"Generally, the younger you are, the more sleep you require," Morse said. "The pattern and duration of sleep changes over time."

Newborn babies need around 14 to 17 hours a day, fragmented across the 24-hour period, she said.

Five-year-old children generally need 10 to 13 hours of sleep at nighttime.

For adolescents, around eight to 10 hours of sleep is needed.

"All of these are given in a range because it's not one size fits all," Morse said.

The quality of a child’s wakefulness during the day can also help parents understand the personalized amount of sleep that is needed.

"If you're noticing impaired quality of wakefulness, which can look like moodiness, irritability, inappropriately falling asleep or reemergence of naps" — that can indicate the need to see a sleep doctor, Morse said.

For parents of children who tend to be more wound-up or anxious, additional activities, like writing in a "worry journal" before bed, can help promote better sleep.

Good sleep hygiene is also important, Morse said — while it might not fix existing sleep problems, it can prevent them from developing.

"Sleep hygiene refers to behaviors prior to bedtime that align with sleepiness," she said.

That might mean having a consistent "wind-down" routine each night that will trigger the child's brain to associate it with going to sleep.

"That can start with simple things like brushing teeth and washing up, putting on pajamas and then doing a relaxing activity, whether it's reading a book, listening to relaxing or lulling music, or doing some light stretching," Morse said.

For parents of children who tend to be more wound-up or anxious, additional activities, like writing in a "worry journal" before bed, can help promote better sleep.