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.

https://www.foxnews.com/health/melatonin-warnings-nearly-half-parents-give-kids-help-them-sleep-experts-urge-caution

Multimodal epilepsy surgery in tuberous sclerosis

Ravindra VM, Karas PJ, Lazaro TT, Coorg R, Awad AW, Patino I, McClernon EE, Clarke D, Cairampoma Whitehead L, Anderson A, Diaz-Medina G, Houck K, Katyayan A, Masters L, Nath A, Quach M, Riviello J, Seto ES, Sully K, Agurs L, Sen S, Handoko M, LoPresti M, Ali I, Curry DJ, Weiner HL. Epilepsy Surgery in Young Children With Tuberous Sclerosis Complex: A Novel Hybrid Multimodal Surgical Approach. Neurosurgery. 2023 Feb 1;92(2):398-406. doi: 10.1227/neu.0000000000002214. Epub 2022 Nov 10. PMID: 36637274.

Abstract

Background: Surgery has become integral in treating children with tuberous sclerosis complex (TSC)-related drug-resistant epilepsy (DRE).

Objective: To describe outcomes of a multimodal diagnostic and therapeutic approach comprising invasive intracranial monitoring and surgical treatment and compare the complementary techniques of open resection and magnetic resonance-guided laser interstitial thermal therapy.

Methods: Clinical and radiographic data were prospectively collected for pediatric patients undergoing surgical evaluation for TSC-related DRE at our tertiary academic hospital. Seizure freedom, developmental improvement, and Engel class were compared.

Results: Thirty-eight patients (20 females) underwent treatment in January 2016 to April 2019. Thirty-five underwent phase II invasive monitoring with intracranial electrodes: 24 stereoencephalography, 9 craniotomy for grid/electrode placement, and 2 grids + stereoencephalography. With the multimodal approach, 33/38 patients (87%) achieved >50% seizure freedom of the targeted seizure type after initial treatment; 6/9 requiring secondary treatment and 2/2 requiring a third treatment achieved >50% freedom. The median Engel class was II at last follow-up (1.65 years), and 55% of patients were Engel class I/II. The mean age was lower for children undergoing open resection (2.4 vs 4.9 years, P = .04). Rates of >50% reduction in seizures (86% open resection vs 88% laser interstitial thermal therapy) and developmental improvement (86% open resection vs 83% magnetic resonance-guided laser interstitial thermal therapy) were similar.

Conclusion: This hybrid approach of using both open surgical and minimally invasive techniques is safe and effective in treating DRE secondary to TSC. Clinical trials focused on treatment method with longer follow-up are needed to determine the optimal candidates for each approach and compare the treatment modalities more effectively.

Pathophysiology of pathological laughing and crying

Lauterbach EC, Cummings JL, Kuppuswamy PS. Toward a more precise, clinically--informed pathophysiology of pathological laughing and crying. Neurosci Biobehav Rev. 2013 Sep;37(8):1893-916. doi: 10.1016/j.neubiorev.2013.03.002. Epub 2013 Mar 18. PMID: 23518269.

Abstract

Involuntary emotional expression disorder (IEED) includes the syndromes of pathological laughing and crying (PLC) and emotional lability (EL). Review of the lesion, epilepsy, and brain stimulation literature leads to an updated pathophysiology of IEED. A volitional system involving frontoparietal (primary motor, premotor, supplementary motor, posterior insular, dorsal anterior cingulate gyrus (ACG), primary sensory and related parietal) corticopontine projections inhibits an emotionally-controlled system involving frontotemporal (orbitofrontal, ventral ACG, anterior insular, inferior temporal, and parahippocampal) projections targeting the amygdala-hypothalamus-periaqueductal gray (PAG)-dorsal tegmentum (dTg) complex that regulates emotional displays. PAG activity is regulated by glutamatergic NMDA, muscarinic M1-3, GABA-A, dopamine D2, norepinephrine alpha-1,2, serotonin 5HT1a, 5HT1b/d, and sigma-1 receptors, with an acetylcholine/GABA balance mediating volitional inhibition of the PAG. Lesions of the volitional corticopontine projections (or of their feedback or processing circuits) can produce PLC. Direct activation of the emotional pathway can result in EL and the laughing or crying of gelastic and dacrystic epilepsy. A criterion-based nosology of PLC and EL subtypes is offered.

Too many people take too many pills

As a pharmacist in a big hospital in Adelaide, Emily Reeve would often see patients overwhelmed by the number of drugs they took each day. “They’d say ‘I take so many medicines that I rattle when I walk’,” she recalls. And she worried that some of the medications these patients were on seemed useless, or even harmful.

Dr Reeve’s patients are not unusual, at least in the rich world. About 15% of people in England take five or more prescription drugs every day. So do 20% of Americans and Canadians aged 40-79. Since the old tend to be sicker, the number of pills a person pops tends to rise over time. Of Americans who are 65 or older, two-thirds take at least five medications each day. In Canada, a quarter of over-65s take ten or more.

Not all those prescriptions are beneficial. Half of older Canadians take at least one that is, in some way, inappropriate. A review of overprescribing in England in 2021 concluded that at least 10% of prescriptions handed out by family doctors, pharmacists and the like should probably not have been issued. And even properly prescribed drugs have side effects. The more medicines someone takes, the more they will experience...

Getting people off drugs is unfamiliar terrain for modern health systems, which are mostly set up to put patients on them. But that is beginning to change. Doctors, pharmacists and nurses are setting up “deprescribing networks” to try to spread the word. (Dr Reeve, now at Monash University, in Melbourne, runs one in Australia.) England’s National Health Service published a plan to reduce overprescribing in 2021. The first international conference on it took place last year, in Denmark...

Other problems are more straightforwardly medical. Some patients end up taking several drugs that affect the same biological pathway. One example is anticholinergics, which suppress the activity of acetylcholine, a neurotransmitter. Several drugs, including some anti-allergy pills, anti-incontinence drugs and tricyclic antidepressants, work this way. But doctors are not always aware of that, says Dr Reeve.

That can cause overdosing. Loading up on anticholinergics can suppress acetylcholine so strongly that it can leave patients stupefied or confused. Often such effects are wrongly ascribed to old age, or to disease. By cutting away problematic drugs, “we’ve had incidents where we have been able to reverse the [incorrect] diagnosis of dementia,” says Barbara Farrell, an academic and pharmacist at the Bruyere Research Institute in Canada.

Overprescribing can become self-reinforcing, says Dr Steinman. Several common drugs block reabsorption of serotonin, another neurotransmitter. Taking too many can cause tremors, insomnia and jerky movements of the arms and legs. Those symptoms are often mistaken for Parkinson’s disease. So drugs for Parkinson’s are added, in what is known as a “prescribing cascade”. These, in turn, can cause low blood pressure and delirium–which are, of course, treated with yet more drugs...

Perhaps the most common reason is that patients are not told when to stop taking a drug, or forget. In America one in five patients who are given gabapentin, a potent painkiller, after surgery are still taking it 90 days later (the recommended maximum is four weeks). Often prescriptions are renewed automatically by other doctors, who see them on a patient’s notes and assume they have to be continued...

Evidence about how to proceed is nevertheless starting to build up. Brochures have been developed in Canada to help patients wean themselves off a number of common drugs. They explain, among other things, what alternatives are available—such as cognitive behavioural therapy rather than sleeping pills for insomnia. Trials suggest they work.

Automated de-prescribing tools and guidelines for some medicines have also been developed in recent years. Medsafer, one such electronic tool, increased the share of hospital patients for whom drugs were de-prescribed from 30% to 55%, according to a study published earlier this year in jama Internal Medicine. The Drug Burden Index, another tool, tallies the cumulative doses of drugs with anticholinergic or sedative effects.

A medical movement, in other words, is beginning. Its potential impact could be considerable. Keith Ridge, England’s chief pharmaceutical officer, drew an ironic but telling comparison in 2021: “With well over a billion items dispensed each year”, he wrote, “there is a huge prize to be gained in improving the health of millions of people—comparable to a new ‘blockbuster’ medicine—if we can only get this right.”

https://www.economist.com/science-and-technology/2023/04/26/too-many-people-take-too-many-pills

Gene therapy and tazarotene/bexarotene therapy for multiple sulfatase deficiency

Promising results from research at The Jackson Laboratory (JAX) and University of Texas Southwestern Medical Center (UTSW) on a gene therapy for the ultra-rare genetic disorder, Multiple Sulfatase Deficiency (MSD), will be presented today during the WORLDSymposium, an annual research conference dedicated to lysosomal diseases. The data paves the way for a gene therapy approach for MSD patients, a very important and exciting step forward for the MSD community.

MSD is an ultra-rare genetic disorder which is often described as “Alzheimer’s in a child,” and leads to premature death, normally before 10 years of age. MSD is caused by mutations in the gene responsible for making formylglycine-generating enzyme, an essential enzyme needed by cells for normal function and to break down cellular waste products, encoded by the SUMF1 gene.

With funding provided by the United MSD Foundation, a parent-led patient advocacy organization that funds research grants for MSD studies, JAX and UTSW partnered to study the SUMf1 gene in mouse models of MSD. The research team utilized a mouse model with the SUMF1 gene “knocked out,” which has similar traits to human MSD patients. While many of the mice die soon after birth, mirroring the short lives of many children with MSD, some of the mice survived past two weeks, providing sufficient time to test possible treatments.

“The experiments were challenging given the early mortality of the mouse model and need to explore several routes of administration and doses,” said Maximiliano Presa , Ph.D., study director at The Jackson Laboratory. “These were big experiments that required a lot of effort, skill and planning by the entire team. The data are encouraging, and we are beyond delighted with the results.”

The researchers used an engineered virus (AAV9) to deliver working copies of the SUMF1 gene into the mouse cells. They tried different delivery methods, locations and time points and found that delivery of the gene through a spinal tap at seven days of age alleviated MSD symptoms. The treated mice showed wide distribution of the SUMF1 gene, no signs of toxicity or neuropathy, improved vision and cardiac function, and no behavioral deficits.

“We are thrilled with these impressive and promising results, and grateful to the scientists and supporters who made them possible,” said Amber Olsen, executive director and founder of the United MSD Foundation. “The United MSD Foundation’s mission is simple: to cure MSD, and this work represents incredible progress toward that cure. Our efforts are now focused on the critical next steps necessary to get gene therapy to children suffering and dying from MSD.”

The data supports that gene replacement therapy could be a therapeutic approach for pediatric subjects, who currently lack any treatment options, and represents a huge milestone for the MSD community.

“We are excited about the results showing successful treatment of mice with MSD, which was the result of a strong collaborative effort between investigators at UTSW, JAX and the United MSD Foundation,” said Steven Gray, Ph.D., associate professor at the University of Texas Southwestern Medical Center.

“MSD is a devastating disease and there are currently no effective treatments for patients. We are highly encouraged by the positive therapeutic response in mice and look forward to further exploring the possible use of this treatment for MSD,” said Rachel Bailey, assistant professor at the University of Texas Southwestern Medical Center.

Through the collaboration with The Jackson Laboratory, UT Southwestern and United MSD Foundation, the MSD community is one step closer to saving the lives of children impacted by this devastating disorder.

https://www.jax.org/news-and-insights/2022/february/promising-data-supports-gene-therapy-for-msd

Schlotawa L, Tyka K, Kettwig M, Ahrens-Nicklas RC, Baud M, Berulava T, Brunetti-Pierri N, Gagne A, Herbst ZM, Maguire JA, Monfregola J, Pena T, Radhakrishnan K, Schröder S, Waxman EA, Ballabio A, Dierks T, Fischer A, French DL, Gelb MH, Gärtner J. Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency. EMBO Mol Med. 2023 Mar 8;15(3):e14837. doi: 10.15252/emmm.202114837. Epub 2023 Feb 15. PMID: 36789546; PMCID: PMC9994482.

Abstract

Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

Strict rest should be avoided after a concussion

Patricios JS, Schneider KJ, Dvorak J, Ahmed OH, Blauwet C, Cantu RC, Davis GA, Echemendia RJ, Makdissi M, McNamee M, Broglio S, Emery CA, Feddermann-Demont N, Fuller GW, Giza CC, Guskiewicz KM, Hainline B, Iverson GL, Kutcher JS, Leddy JJ, Maddocks D, Manley G, McCrea M, Purcell LK, Putukian M, Sato H, Tuominen MP, Turner M, Yeates KO, Herring SA, Meeuwisse W. Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport-Amsterdam, October 2022. Br J Sports Med. 2023 Jun;57(11):695-711. doi: 10.1136/bjsports-2023-106898. PMID: 37316210.

Abstract

For over two decades, the Concussion in Sport Group has held meetings and developed five international statements on concussion in sport. This 6th statement summarises the processes and outcomes of the 6th International Conference on Concussion in Sport held in Amsterdam on 27-30 October 2022 and should be read in conjunction with the (1) methodology paper that outlines the consensus process in detail and (2) 10 systematic reviews that informed the conference outcomes. Over 3½ years, author groups conducted systematic reviews of predetermined priority topics relevant to concussion in sport. The format of the conference, expert panel meetings and workshops to revise or develop new clinical assessment tools, as described in the methodology paper, evolved from previous consensus meetings with several new components. Apart from this consensus statement, the conference process yielded revised tools including the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), as well as a new tool, the Sport Concussion Office Assessment Tool-6 (SCOAT6, Child SCOAT6). This consensus process also integrated new features including a focus on the para athlete, the athlete's perspective, concussion-specific medical ethics and matters related to both athlete retirement and the potential long-term effects of SRC, including neurodegenerative disease. This statement summarises evidence-informed principles of concussion prevention, assessment and management, and emphasises those areas requiring more research.

_______________________________________________________________________________

Strict rest should be avoided after a concussion, but light-intensity physical activity, such as walking, can help recovery. Screen use should also be limited in the first 48 hours following the injury, according to a new statement released by the Concussion in Sport Group published in the British Journal of Sports Medicine. The new guidelines come following the organization’s 6th International Conference on Concussion in Sport, held in Amsterdam from October 27 to 30, 2022.

The new guidelines also updated the definition of concussion, though “work continues toward a unified conceptual and operational definition.” The consensus statement also highlighted sport-specific strategies for prevention, including policy changes to reduce collisions (such as suggesting disallowing body-checking in hockey), neuromuscular training, and the implementation of optimal concussion management strategies to decrease recurrent concussion rates.

The conference also produced updated versions of the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), designed for use within the first 72 hours (and up to 1 week) following injury. Additionally, new office tools, the Sport Concussion Office Assessment Tool-6 (SCOAT6) and Child SCOAT6, were developed for post-72-hour evaluations and subsequent weeks.

The statement updated return-to-learn and return-to-sport strategies, and underscored the benefits of physical activity and aerobic exercise as early interventions. For athletes experiencing neck pain, headaches, dizziness, and/or balance issues, cervicovestibular rehabilitation was recommended.

For individuals with persisting symptoms lasting more than 4 weeks, a multimodal clinical assessment using standardized symptom rating scales was proposed.

The potential long-term effects of sports-related concussions and repetitive head impacts, sex-based differences in concussion prevention and management, concussion diagnosis and management in para-athletes, and concussions in children aged 5 to 12 years were acknowledged as areas requiring dedicated research, the Concussion in Sport Group noted.

https://www.hmpgloballearningnetwork.com/site/neuro/news/no-strict-rest-after-concussion-and-other-new-guidelines-released

Euthanasia for autism and intellectual handicaps

Netherlands programs have euthanized otherwise healthy individuals with autism and intellectual handicaps in recent years, researchers have found. 

Five individuals under the age of 30, who cited autism as a factor in their decision to seek legal euthanasia, are among the cases reviewed by specialists at the U.K.'s Kingston University. 

"Factors directly associated with intellectual disability and/or ASD were the sole cause of suffering described in 21% of cases and a major contributing factor in a further 42% of cases," Kingston University's report on the issue found. 

The study noted that in many cases, doctors determined there was "no prospect of improvement" for intellectually challenged individuals because there is no treatment for their handicap.

"Reasons for the EAS [euthanasia and physician-assisted suicide] request included social isolation and loneliness (77%), lack of resilience or coping strategies (56%), lack of flexibility (rigid thinking or difficulty adapting to change) (44%) and oversensitivity to stimuli (26%). In one-third of cases, physicians noted there was ‘no prospect of improvement’ as ASD and intellectual disability are not treatable," the study reads.

Palliative care specialist Irene Tuffrey-Wijne — one of the lead authors of the Kingston University report — found Dutch doctors were legally killing patients who sought their own euthanasia because their intellectual disability or mental condition prevented them from leading a normal life, according to The Associated Press.

One record includes the case of a Dutch woman in her 30s with autism and borderline personality disorder. Doctors determined her afflictions prevented her from maintaining relationships and made forming connections with others "too difficult."

"There’s no doubt in my mind these people were suffering," Tuffrey-Wijne said. "But is society really OK with sending this message, that there’s no other way to help them, and it’s just better to be dead?"

Dutch psychologist Dr. Bram Sizoo expressed horror at the trend of autistic youths seeking assisted suicide and euthanasia's expanding acceptance.

"Some of them are almost excited at the prospect of death," Sizoo said. "They think this will be the end of their problems and the end of their family’s problems."

The Royal Dutch Medical Association has left the decision of who qualifies for assisted suicide up to medical professionals with few hard guidelines or rules.

https://www.foxnews.com/world/netherlands-euthanizing-autistic-intellectually-handicapped-people-researcher-finds

The ironically named Court of Protection. More end-of-life humanity in the UK

A UK court has ruled a 19-year-old critically ill female patient with a rare disorder cannot make her own decisions about continuing her medical care, as her family battles her doctors' desire to stop treatment and pursue end-of-life care.

The teen, whose identity has been anonymized as "ST" by the court, has a rare genetic mitochondrial disease that is progressively degenerative, according to court documents. Her condition is similar to that of Charlie Gard, the infant whose story drew global headlines in 2017. Charlie's parents lost a bid to bring him to the U.S. for an experimental treatment for his critical condition and he died after the hospital withdrew life-saving care after a months-long high profile legal battle.

Despite previously being a student studying for her A-levels (short for advanced levels), the 19-year-old girl has spent the past year in the ICU, dependent on a ventilator and a feeding tube. She requires regular dialysis due to chronic kidney damage from her disease. "ST" is currently fighting the hospital to be allowed to travel to Canada for an experimental treatment to treat her disease.

The Christian Legal Centre, which is advocating for the patient, argues her case is different than Gard's because she is conscious and able to communicate and argue in her defense.

But her doctor believe "ST" is "actively dying" and has no hope of a cure to resume life outside intensive care. They are asking the court to end her dialysis treatments and pursue palliative care instead. The hospital told the court the 19-year-old is incapable of making decisions about her future medical care because she is under the "delusion" that her death is not imminent.

The teen, who comes from a strong Christian family, confessed she realizes the treatment may not help extend her life but wants to keep fighting.

"This is my wish. I want to die trying to live. We have to try everything," she told clinicians, according to court documents.

Her family has spent their entire life savings to treat the girl, the Christian Legal Centre said, and wants to go to the public to raise funds for the expensive treatment, but cannot due to a "transparency order" requested by the hospital which bars reporting any information which might identify "ST", her family, or the hospital.

The girl's family described the long battle with the hospital as "a year of continuous torture" for them.

"Not only are we anxious about our beloved daughter’s fight for survival, but we have also been cruelly gagged from being able to speak about her situation. We are not allowed to ask people for prayers or for help which she desperately needs. It is a matter of life and death for our daughter to raise money for treatment in Canada, so these arbitrary reporting restrictions are literally killing her," they said via legal representation.

In court this week, a judge determined the teen "is able to communicate reasonably well with her doctors with assistance from her mother and, on occasion, speech therapists." Two psychiatrists assessed the teen was capable of making decisions about her future care for herself.

However, the judge said that, "ST" was mentally incapable of making decisions for herself because "she does not believe the information she has been given by her doctors." The judge ruled that decisions about ST's further care should be determined by the Court of Protection based on an assessment of her best interests.

"We are shocked to be told by the judge that our daughter does not have capacity to make decisions for herself after all the experts have said that she does. We are very distressed by this injustice, and we hope that, by Jesus’s grace, this will be corrected on appeal," the family of the patient said. 

Andrea Williams, the Chief Executive of Christian Legal Centre, blasted the transparency order and called the case "profoundly disturbing."

"This profoundly disturbing case demonstrates the urgent need for an overhaul into how end-of-life decisions are made in the NHS and the Courts," she said.

"What can be more natural or rational for a seriously ill 19-year-old than to leave no stone unturned and to take every chance of survival? ST has wanted to tell her story to the world in order to try and access further treatment but has been prevented from doing so by the ironically named Court of Protection," she said in a statement.

The NHS did not respond to a request for comment.

https://www.foxnews.com/media/uk-court-rules-teen-rare-disorder-incapable-making-decisions-care-begging-live

See the video, Charlie Gard's father: So sorry we couldn't save you. https://www.foxnews.com/video/5519176818001

Clinical spectrum and treatment outcomes of patients with developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep

Tchah N, Yang D, Kim HD, Lee JS, Kim SH, Kang HC. Clinical Spectrum and Treatment Outcomes of Patients with Developmental and/or Epileptic Encephalopathy with Spike-and-Wave Activation in Sleep. Ann Child Neurol. 2022;30(4):189-196.

Abstract

Purpose
Developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (D/EE-SWAS) is a spectrum of conditions characterized by various phenotypes of cognitive, linguistic, and behavioral regression associated with spike-and-wave activation in sleep. We aimed to investigate the phenotypic spectrum and treatment outcomes of pediatric patients with D/EE-SWAS.

Methods
We retrospectively analyzed the medical records of pediatric patients diagnosed with D/EE-SWAS and treated at Severance Children’s Hospital from 2006 to 2022. We extracted information from their medical records on electroencephalography before and after treatment, types of treatment, seizure frequency, and developmental profiles. The primary outcome was reduction of the spike-wave index on electroencephalography after treatment.

Results
Twenty-one patients with a median age of 5.3 years (interquartile range, 4.1 to 6.6) at diagnosis were included. Ten patients had delayed development. The patients received various anti-seizure medications. Fourteen received long-term, high-dose steroid therapy, 10 were placed on a ketogenic diet, four received intravenous steroid pulse therapy, and one each was treated with intravenous immunoglobulin and cannabidiol. The most effective treatments were steroid therapy and a ketogenic diet, which were also effective in reducing seizures and improving cognition. Side effects during treatment were transient and treatable.

Conclusion
We described the clinical spectrum of pediatric patients with D/EE-SWAS. Steroid therapy and a ketogenic diet can be considered effective therapeutic options for patients with D/EE SWAS.

Iron and tic disorders

Inspired by a patient

Avrahami M, Barzilay R, HarGil M, Weizman A, Watemberg N. Serum Ferritin Levels Are Lower in Children With Tic Disorders Compared with Children Without Tics: A Cross-Sectional Study. J Child Adolesc Psychopharmacol. 2017 Mar;27(2):192-195. doi: 10.1089/cap.2016.0069. Epub 2016 Aug 22. PMID: 27548271.

Abstract

Objectives: Alteration in peripheral iron indices has been reported in a number of movement disorders, particularly Parkinson's disease. We hypothesized that iron stores may be diminished in children at an early stage of tic disorder.

Methods: Using data retrieved from electronic medical records, we compared serum ferritin levels, an indicator of body iron store balance, in drug-naive children diagnosed for the first time with tic disorder (study group; N = 47, 32 boys/15 girls, aged 8.66 ± 3.17 years) compared to age- and sex-matched children with headaches (comparison group, n = 100, 62 boys/38 girls, aged 9.51 ± 3.15 years) treated in the same pediatric neurological clinic.

Results: Mean serum ferritin levels were significantly lower (-32%, p = 0.01) in the tic disorder group compared to the headache group. No significant differences were detected in circulatory hemoglobin, iron, transferrin, and platelet count between the two groups.

Conclusion: Our findings suggest that body iron stores may be reduced in children with recent-onset tic disorder.

Ghosh D, Burkman E. Relationship of serum ferritin level and tic severity in children with Tourette syndrome. Childs Nerv Syst. 2017 Aug;33(8):1373-1378. doi: 10.1007/s00381-017-3424-z. Epub 2017 May 3. PMID: 28470381.

Abstract

Purpose: Tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS). Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in Tourette syndrome (TS). The purpose of this study was to evaluate the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS.

Methods: Children <18 years, diagnosed with TS during 2009-2015, were reviewed. Only those with serum ferritin testing were included. The following data were collected: tic severity, impact on life, medication, comorbidities, blood count, and serum ferritin at diagnosis and follow-up.

Results: In fifty-seven patients, M:F = 2:1, serum ferritin was 48.0 ± 33.28 ng/mL, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6. Serum ferritin was not influenced by comorbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (P > 0.16). Thirty-eight percent with low serum ferritin (≤50 ng/mL) (n = 37) had severe tics (>5 composite score), compared with 25% in normal ferritin group (n = 20). Over 6-12 months, tic severity score improved in both iron treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron.

Conclusions: Our data suggest iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. Iron supplementation showed a trend towards improvement of tic severity upon follow-up. We suggest a double-blind, placebo-controlled prospective study to reach a definite conclusion.

Kanaan AS, Yu D, Metere R, Schäfer A, Schlumm T, Bilgic B, Anwander A, Mathews CA, Scharf JM, Müller-Vahl K, Möller HE. Convergent imaging-transcriptomic evidence for disturbed iron homeostasis in Gilles de la Tourette syndrome. Neurobiol Dis. 2023 Aug 2;185:106252. doi: 10.1016/j.nbd.2023.106252. Epub ahead of print. PMID: 37536382.

Abstract

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric movement disorder with reported abnormalities in various neurotransmitter systems. Considering the integral role of iron in neurotransmitter synthesis and transport, it is hypothesized that iron exhibits a role in GTS pathophysiology. As a surrogate measure of brain iron, quantitative susceptibility mapping (QSM) was performed in 28 patients with GTS and 26 matched controls. Significant susceptibility reductions in the patients, consistent with reduced local iron content, were obtained in subcortical regions known to be implicated in GTS. Regression analysis revealed a significant negative association of tic scores and striatal susceptibility. To interrogate genetic mechanisms that may drive these reductions, spatially specific relationships between susceptibility and gene-expression patterns from the Allen Human Brain Atlas were assessed. Correlations in the striatum were enriched for excitatory, inhibitory, and modulatory neurochemical signaling mechanisms in the motor regions, mitochondrial processes driving ATP production and iron‑sulfur cluster biogenesis in the executive subdivision, and phosphorylation-related mechanisms affecting receptor expression and long-term potentiation in the limbic subdivision. This link between susceptibility reductions and normative transcriptional profiles suggests that disruptions in iron regulatory mechanisms are involved in GTS pathophysiology and may lead to pervasive abnormalities in mechanisms regulated by iron-containing enzymes.

Tang CY, Wen F. Serum ferritin levels in children with attention deficit hyperactivity disorder and tic disorder. World J Clin Cases. 2022 Aug 6;10(22):7749-7759. doi: 10.12998/wjcc.v10.i22.7749. PMID: 36158507; PMCID: PMC9372851.

Abstract

Background: Iron plays an important role in neurodevelopmental functions in the brain. Serum ferritin levels are different in children with attention deficit hyperactivity disorder and tic disorder than in healthy children.

Aim: To explore the current status of iron deficiency in children with neurodevelopmental disorders and its sex and age effects.

Methods: A total of 1565 children with attention deficit hyperactivity disorder (ADHD), 1694 children with tic disorder (TD), 93 children with ASD and 1997 healthy control children were included between January 1, 2020, and December 31, 2021 at Beijing Children's Hospital. We describe the differences in age levels and ferritin levels between different disease groups and their sex differences. The differences between the sexes in each disease were analyzed using the t test. The incidence rate of low serum ferritin was used to describe the differences between different diseases and different age groups. A chi-square test was used to analyze the difference in the incidence of low serum ferritin between the disease group and the control group. Analysis of variance was used for comparisons between subgroups, and regression analysis was used for confounding factor control.

Results: A total of 1565 ADHD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 36.82 ± 20.64 μg/L and 35.64 ± 18.56 μg/L, respectively. A total of 1694 TD patients aged 5-12 years were included in this study, and the average serum ferritin levels of male and female children were 35.72 ± 20.15 μg/L and 34.54 ± 22.12 μg/L, respectively. As age increased, the incidence of low serum ferritin in ADHD and TD first decreased and then increased, and 10 years old was the turning point of rising levels. The incidence of ADHD with low serum ferritin was 8.37%, the incidence of TD with low serum ferritin was 11.04%, and the incidence of the healthy control group with low serum ferritin was 8.61%, among which male children with TD accounted for 9.25% and female children with TD accounted for 11.62%. There was a significant difference among the three groups (P < 0.05). In addition, there were 93 children with ASD with an average serum ferritin level of 30.99 ± 18.11 μg/L and a serum ferritin incidence of 15.05%.

Conclusion: In conclusion, low serum ferritin is not a risk factor for ADHD or TD. The incidence of low serum ferritin levels in children with ADHD and TD between 5 and 12 years old decreases first and then increases with age.

Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Bai YM. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. BMC Psychiatry. 2013 Jun 4;13:161. doi: 10.1186/1471-244X-13-161. PMID: 23735056; PMCID: PMC3680022.

Abstract

Background: A great deal of evidence has shown that iron is an important component in cognitive, sensorimotor, and social-emotional development and functioning, because the development of central nervous system processes is highly dependent on iron-containing enzymes and proteins. Deficiency of iron in early life may increase the risk of psychiatric morbidity.

Methods: Utilizing the National Health Insurance Database from 1996 to 2008, children and adolescents with a diagnosis of IDA were identified and compared with age and gender-matched controls (1:4) in an investigation of the increased risk of psychiatric disorders.

Results: A total of 2957 patients with IDA, with an increased risk of unipolar depressive disorder (OR = 2.34, 95% CI = 1.58 ~ 3.46), bipolar disorder (OR = 5.78, 95% CI = 2.23 ~ 15.05), anxiety disorder (OR = 2.17, 95% CI = 1.49 ~ 3.16), autism spectrum disorder (OR = 3.08, 95% CI = 1.79 ~ 5.28), attention deficit hyperactivity disorder (OR = 1.67, 95% CI = 1.29 ~ 2.17), tic disorder (OR = 1.70, 95% CI = 1.03 ~ 2.78), developmental delay (OR = 2.45, 95% CI = 2.00 ~ 3.00), and mental retardation (OR = 2.70, 95% CI = 2.00 ~ 3.65), were identified. A gender effect was noted, in that only female patients with IDA had an increased OR of bipolar disorder (OR = 5.56, 95% CI = 1.98 ~ 15.70) and tic disorder (OR = 2.95, 95% CI = 1.27 ~ 6.86).

Conclusion: Iron deficiency increased the risk of psychiatric disorders, including mood disorders, autism spectrum disorder, attention deficit hyperactivity disorder, and developmental disorders. Further study is required to clarify the mechanism in the association between IDA and psychiatric disorder.

Efficiency of brivaracetam in a tertiary referral epilepsy center.

Steinhoff BJ, Bacher M, Bucurenciu I, Hillenbrand B, Intravooth T, Kornmeier R, Kurth C, Stockinger J, Staack AM. Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy-A monocenter survey. Seizure. 2017 May;48:11-14. doi: 10.1016/j.seizure.2017.03.010. Epub 2017 Mar 18. PMID: 28364655.

Abstract

Purpose: To assess the efficiency of brivaracetam under real-world conditions in a tertiary referral epilepsy center.

Methods: We consecutively collected patients treated at our center with brivaracetam (BRV). After a minimum observation period of six months we retrospectively analyzed the efficiency of BRV.

Results: Data of 101 patients (mean age 42 years, range 18-81 years, 54 females,) were analyzed. The median number of antiepileptic drugs (AEDs) used prior to BRV was 10 (range 2-18). The initial dose of BRV was at least 50mg per day, the mean maintenance dose at cut-off was 168.6mg (median 200mg, range 50-400mg). Efficacy data were assessed for the last three months or at the time of the last observation carried forward if BRV had been discontinued prematurely. Responder rate was 27.8% (n=28) with 7% seizure-free patients. Adverse events (AEs) occurred in 37 patients (37%). Most frequent AEs were dizziness (16%) and somnolence (11%). Psychiatric adverse events comprised irritability, aggression, depression and psychosis in single cases. Retention rate after six months was 51.5%. Main reason for discontinuation was a lack of efficacy. In 43 cases LEV and BRV were switched. The switch was performed abruptly without complications. In 26 cases (60%) BRV was discontinued and re-switched to LEV within weeks, mainly due to a lack of better efficacy. After the switch from LEV to BRV we even saw an aggravation both of seizure frequency and severity in 5 cases. Retention rate in patients who had not been on LEV was 57%.

Conclusion: In our hands BRV appeared to be well tolerated and easy to handle. The retention rate was influenced by patients who were switched from LEV and re-switched because BRV was not more efficient. Switching from and re-switching to LEV was easy.

1p36 deletion syndrome

Inspired by a patient

Jacquin C, Landais E, Poirsier C, Afenjar A, Akhavi A, Bednarek N, Bénech C, Bonnard A, Bosquet D, Burglen L, Callier P, Chantot-Bastaraud S, Coubes C, Coutton C, Delobel B, Descharmes M, Dupont JM, Gatinois V, Gruchy N, Guterman S, Heddar A, Herissant L, Heron D, Isidor B, Jaeger P, Jouret G, Keren B, Kuentz P, Le Caignec C, Levy J, Lopez N, Manssens Z, Martin-Coignard D, Marey I, Mignot C, Missirian C, Pebrel-Richard C, Pinson L, Puechberty J, Redon S, Sanlaville D, Spodenkiewicz M, Tabet AC, Verloes A, Vieville G, Yardin C, Vialard F, Doco-Fenzy M. 1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients. Am J Med Genet A. 2023 Feb;191(2):445-458. doi: 10.1002/ajmg.a.63041. Epub 2022 Nov 11. PMID: 36369750; PMCID: PMC10100125.

Abstract

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

Greco M, Ferrara P, Farello G, Striano P, Verrotti A. Electroclinical features of epilepsy associated with 1p36 deletion syndrome: A review. Epilepsy Res. 2018 Jan;139:92-101. doi: 10.1016/j.eplepsyres.2017.11.016. Epub 2017 Dec 2. PMID: 29212048.

Abstract

1p36 terminal deletion is a recently recognized syndrome with multiple congenital anomalies and intellectual disability. It occurs approximately in 1 out of 5000 to 10,000 live births and is the most common subtelomeric microdeletion observed in human. Medical problems commonly caused by terminal deletions of 1p36 include developmental delay, intellectual disability, seizures, vision problems, hearing loss, short stature, brain anomalies, congenital heart defects, cardiomyopathy, renal anomalies and distinctive facial features. Although the syndrome is considered clinically recognizable, there is significant phenotypic variation among affected individuals. Genotype-phenotype correlation in this syndrome is complicated, because of the similar clinical evidence seen in patients with different deletion sizes. We review 34 scientific articles from 1996 to 2016 that described 315 patients with 1p36 delection syndrome. The aim of this review is to find a correlation between size of the 1p36-deleted segments and the neurological clinical phenotypes with the analysis of electro-clinical patterns associated with chromosomal aberrations, that is a major tool in the identification of epilepsy susceptibility genes. Our finding suggest that developmental delay and early epilepsy are frequent findings in 1p36 deletion syndrome that can contribute to a poor clinical outcome for this reason this syndrome should be searched for in patients presenting with infantile spasms associated with a hypsarrhythmic EEG, particulary if they are combined with dismorphic features, severe hypotonia and developmental delay.

Carter LB, Battaglia A, Cherry A, Manning MA, Ruzhnikov MR, Bird LM, Dowsett L, Graham JM Jr, Alkuraya FS, Hashem M, Dinulos MB, Vallee S, Adam MP, Glass I, Beck AE, Stevens CA, Zackai E, McDougall C, Keena B, Peron A, Vignoli A, Seaver LH, Slavin TP, Hudgins L. Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy. Am J Med Genet A. 2019 Aug;179(8):1543-1546. doi: 10.1002/ajmg.a.61266. Epub 2019 Jun 17. PMID: 31207089; PMCID: PMC7254578.

Abstract

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

Rocha CF, Vasques RB, Santos SR, Paiva CL. Mini-Review: Monosomy 1p36 syndrome: reviewing the correlation between deletion sizes and phenotypes. Genet Mol Res. 2016 Feb 22;15(1). doi: 10.4238/gmr.15017942. PMID: 26910004.

Abstract

The major clinical features of monosomy 1p36 deletion are developmental delay and hypotonia associated with short stature and craniofacial dysmorphisms. The objective of this study was to review the cases of 1p36 deletion that was reported between 1999 and 2014, in order to identify a possible correlation between the size of the 1p36-deleted segment and the clinical phenotype of the disease. Scientific articles published in the (National Center for Biotechnology Information; NCBI http://www.ncbi.nlm.nih.gov/pubmed) and Scientific Electronic Library Online (www.scielo.com.br) databases were searched using key word combinations, such as "1p36 deletion", "monosomy 1p36 deletion", and "1p36 deletion syndrome". Articles in English or Spanish reporting the correlation between deletion sizes and the respective clinical phenotypes were retrieved, while letters, reviews, guidelines, and studies with mouse models were excluded. Among the 746 retrieved articles, only 17 (12 case reports and 5 series of cases), comprising 29 patients (9 males and 20 females, aged 0 months (neonate) to 22 years) bearing the 1p36 deletions and whose clinical phenotypes were described, met the inclusion criteria. The genotype-phenotype correlation in monosomy 1p36 is a challenge because of the variability in the size of the deleted segment, as well as in the clinical manifestations of similar size deletions. Therefore, the severity of the clinical features was not always associated with the deletion size, possibly because of the other influences, such as stochastic factors, epigenetic events, or reduced penetration of the deleted genes.

Shimada S, Shimojima K, Okamoto N, Sangu N, Hirasawa K, Matsuo M, Ikeuchi M, Shimakawa S, Shimizu K, Mizuno S, Kubota M, Adachi M, Saito Y, Tomiwa K, Haginoya K, Numabe H, Kako Y, Hayashi A, Sakamoto H, Hiraki Y, Minami K, Takemoto K, Watanabe K, Miura K, Chiyonobu T, Kumada T, Imai K, Maegaki Y, Nagata S, Kosaki K, Izumi T, Nagai T, Yamamoto T. Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications. Brain Dev. 2015 May;37(5):515-26. doi: 10.1016/j.braindev.2014.08.002. Epub 2014 Aug 27. PMID: 25172301.

Abstract

Objective: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features.

Method: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined.

Results: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes.

Conclusion: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

Delayed response to pyridoxine in pyridoxine-dependent epilepsy

Olivier Fortin, Kelsey Christoffel, Youssef Kousa, Ilana Miller, Eyby Leon, Kelsey Donoho, Sarah B. Mulkey, Tayyba Anwar. Pearls & Oy-sters: Delayed Response to Pyridoxine in Pyridoxine-Dependent Epilepsy. Neurology Aug 2023, 10.1212/WNL.0000000000207829; DOI: 10.1212/WNL.0000000000207829

Abstract

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred five days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found.

Peer victimization and suicidality associated with higher headache frequency

Christelle Nilles, Jeanne VA Williams, Scott Patten, Tamara Pringsheim, Serena L. Orr. Association Between Peer Victimization, Gender Diversity, Mental Health, and Recurrent Headaches in Adolescents: A Canadian Population-Based Study. Neurology Aug 2023, 10.1212/WNL.0000000000207738; DOI: 10.1212/WNL.0000000000207738

Abstract

Background and objectives: It is unknown whether bullying and gender diversity are associated with increased headache frequency in adolescents. Our study aimed to assess the association between peer victimization, gender diversity, and frequent recurrent headaches in adolescents, while controlling for age, sex, socioeconomic status, and potential confounders (mood and anxiety disorders, suicidality).


Methods: This was a cross-sectional observational study of adolescents aged 12-17 using data from a Canadian population-based health survey. Headache frequency was dichotomized into ‘≤once/week’ or ‘>once/week’ (i.e. frequent recurrent headaches). Logistic regression was used to quantify the association between frequent peer victimization (overt or relational), gender diversity (female sex at birth+male gender, male sex at birth+female gender, or gender diverse), mood/anxiety disorder, suicidality, and the odds of frequent recurrent headaches. The fully adjusted multivariable logistic regression model included all exposures and was controlled for age, sex, and socioeconomic status. Bootstrap replicate weighting was used to account for survey design effects.

Results: There were an estimated 2,268,840 eligible participants (weighted sample size) (mean age=14.4y, 48.8% females, 0.5% gender diverse) and 11.2% reported frequent recurrent headaches. Frequent recurrent headaches were associated with older age (OR=1.26 per year of age, 95%CI=1.20-1.31), female sex (OR=2.89, 95%CI=2.47-3.37), and being gender diverse (OR=3.30, 95%CI=1.64-6.63, adjusted for age/sex). Youth with frequent headaches had higher odds of experiencing both overt and relational bullying compared to peers (OR=2.69, 95%CI=2.31-3.14, and OR=3.03, 95%CI=2.58-3.54, adjusted for age/sex). In the fully adjusted model, frequent headaches were no longer associated with gender diversity (OR=1.53, 95%CI=0.63-3.69), but were still associated with frequent overt and relational peer victimization (OR=1.82, 95%CI=1.41-2.34, and OR=1.54, 95%CI=1.17-2.03, respectively), suicidality (OR=1.83, 95%CI=1.44-2.32), and having a mood or anxiety disorder (OR=1.50, 95%CI=1.01-2.21, and OR=1.74, 95%CI=1.24-2.45, respectively). In a model adjusted for age, sex, and mood/anxiety disorders, the risk of suicidality increased incrementally with headache frequency.

Discussion: Peer victimization and suicidality may be associated with higher headache frequency in adolescents with headaches, independently of mood and anxiety symptoms. Gender diverse adolescents may have a higher risk of experiencing frequent headaches as compared to cisgender peers, and this may be explained by associated psychosocial factors (anxiety, depression, suicidality, peer victimization).

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Adolescents who have been bullied or who have considered or attempted suicide may be more likely to experience frequent headaches than their peers who have not experienced bullying or suicidality, according to study results published online ahead of print in Neurology.

“Headaches are a common problem for teenagers, but our study looked beyond the biological factors to also consider the psychological and social factors that are associated with headaches,” said study author Serena L. Orr, MD, MSc, of the University of Calgary in Canada. “Our findings suggest that bullying and attempting or considering suicide may be linked to frequent headaches in teenagers, independent of mood and anxiety disorders.”

More than 2.2 million Canadian adolescents, ages 12 through 17, were included in the observational study. Participants answered question about their headache frequency, mental health, peer victimization, and suicidality.

Some 11% of adolescents reported having frequent, recurring headaches, defined as one or more headaches per week. Meanwhile, 25% of participants reported being victims of frequent overt bullying, which spanned physical and verbal aggression as well as virtual threats, and 17% reported being victims of frequent relational bullying, such as exclusion, rumors, and having harmful information about them posted online. According to the study, 17% of participants reported considering or attempting suicide.

Analysis indicated that adolescents with frequent headaches were nearly 3 times more likely to have experienced bullying compared with their peers. Teens who had been bullied or had suicidal thoughts or attempts were nearly twice as likely to have frequent headaches. Teens with mood disorders were 50% more likely, and teens with anxiety disorders were 74% more likely, to have frequent headaches compared with peers.

A third of teens with frequent headaches had suicidal thoughts or attempts compared with 14% of teens without frequent headaches.

An association between gender diversity and frequent headaches dissolved after researchers adjusted for factors including being bullied or having a diagnosed mood or anxiety disorder.

“Though gender diverse teens appear to have a higher risk of frequent, recurring headaches, this association disappears after controlling for bullying, anxiety, depression, and suicidal tendencies, suggesting that perhaps gender diversity is not, in and of itself, related to frequent headaches, but that the psychosocial factors associated with it may explain this link,” said Dr Orr. “This is important information because these factors are preventable and treatable, and as such, must be examined further.”

https://www.hmpgloballearningnetwork.com/site/neuro/news/teens-headaches-report-increased-rates-bullying-suicidality

Foreign accent syndrome 4

Broderick A, Labriola MK, Shore N, et al. Foreign accent syndrome as a heralding manifestation of transformation to small cell neuroendocrine prostate cancer. BMJ Case Reports CP 2023;16:e251655.

Abstract

A man in his 50s with metastatic hormone-sensitive prostate cancer, receiving androgen deprivation therapy and abiraterone acetate/prednisone, presented with an uncontrollable ‘Irish brogue’ accent despite no Irish background, consistent with foreign accent syndrome (FAS). He had no neurological examination abnormalities, psychiatric history or MRI of the brain abnormalities at symptom onset. Imaging revealed progression of his prostate cancer, despite undetectable prostate-specific antigen levels. Biopsy confirmed transformation to small cell neuroendocrine prostate cancer (NEPC). Despite chemotherapy, his NEPC progressed resulting in multifocal brain metastases and a likely paraneoplastic ascending paralysis leading to his death. We report FAS as the presenting manifestation of transformation to small cell NEPC, a previously undescribed phenomenon. His presentation was most consistent with an underlying paraneoplastic neurological disorder (PND), despite a negative serum paraneoplastic panel. This report enhances the minimal existing literature on FAS and PNDs associated with transformed NEPC.

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Key Takeaways

Recently, a man suddenly woke up with an Irish accent after being diagnosed with cancer.

Foreign accent syndrome is a rare disorder that can be caused by tumors, brain injury, and other conditions.

A full medical care team will usually be needed to help a patient with foreign accent syndrome.

Imagine suddenly speaking with an accent that sounds like you were born and raised in, say, Italy or Jamaica. That’s what happens to patients with foreign accent syndrome (FAS), a rare condition that researchers are striving to better understand.

In a recent report of FAS published in BMJ Case Reports, researchers out of Duke University in Durham, North Carolina, and Carolina Urologic Research Center in South Carolina shared the story of a man in his 50s who developed the syndrome after a cancer diagnosis.

The individual in the case report was diagnosed with metastatic hormone-sensitive prostate cancer. Twenty months after his diagnosis, he developed “an uncontrollable ‘Irish brogue’ accent despite no Irish background,” according to the report’s authors. The man had never been to Ireland and had never spoken with an Irish accent prior to this point.

“He had no neurological examination abnormalities, psychiatric history, or MRI of the brain abnormalities at symptom onset,” the report stated.

What is foreign accent syndrome?

Foreign accent syndrome is real, although it’s rare. According to the Callier Center for Communication Disorders at the University of Texas at Dallas, FAS (which has also been referred to as pseudo-FAS and dysprosody) is a speech disorder that causes a sudden change to a person’s speaking speech patterns.

The onset of FAS can be sudden or gradual. “In [the case of the man in the report], it developed over days but worsened. It can be very quick,” Andrew J. Armstrong, MD, MSc, and Medical Oncologist at Duke Cancer Center, tells MDLinx.com.

The first case of FAS was reported in 1907. Since, there have been around 112 known cases, with FAS affecting people in multiple countries and in multiple ways. The accents in FAS are all over the spectrum, with people whose American accents became Caribbean or whose Japanese accents became Chinese.

FAS patients’ accents are perceived as “foreign,” largely due to changes in the “timing, intonation, and tongue placement” of the speaker. For example, some FAS patients may put stress on different syllables, while others have trouble pronouncing consonants clearly.

So when people with FAS speak in a French or Irish accent, for example, it’s not really French or Irish. “Although it is called foreign accent syndrome, the accents heard are not true accents of any specific language. Instead, they tend to sound like a mix of different accents or dialects,” says Nick Bach, PsyD.

The causes of FAS

“Stroke, trauma, brain tumors, and psychiatric conditions [are the main causes] of FAS,” says Armstrong. Cases of FAS have also been reported in psychiatry, in cases of mania, bipolar disorder, and schizophrenia, among other conditions. The researchers believe that paraneoplastic neurological disorder (PND)—effects caused by systemic malignancies that impact the nervous system—was ultimately the cause of FAS in the case report's individual. “The term PND is reserved for those disorders that are caused by an autoimmune response directed against antigens common to the tumor and nerve cells,” according to the Journal of Neurology, Neurosurgery & Psychiatry. According to the report, the patient’s biopsy revealed small-cell neuroendocrine prostate cancer (NEPC), which progressed despite treatment and led to multifocal brain metastases and paraneoplastic ascending paralysis.

The report suggests that this was the first case of FAS found in a patient with prostate cancer but the third case in a patient with malignancy.

“We have no other clear explanation other than a paraneoplastic syndrome given the timing, persistence of symptoms, lack of psychiatric conditions or metastases or lesions in the brain at the time of onset,” says Armstrong. “We provide this report in case future patients may be identified and hopefully a specific antibody may be identified to better explain why this happened.”

Treating FAS and supporting patients

Diagnosis of FAS will require testing your patient’s language skills and recording their speech patterns, as well as EEG, MRI, PT, CT, or PET scans. Treating the underlying issue—whether that be a neurological disorder or a tumor, for example—is the recommended form of treatment, Armstrong says. Treating FAS takes a village, and would ideally include a speech-language pathologist, a neurologist, a radiologist, a neuropsychologist, and a psychologist. Some cases of FAS have resolved without intervention, while others evolve or remain, according to ASHAWire.

While medical treatment is key, treating the psychological impact of FAS is also necessary, as developing a new accent can cause a loss of identity.Reader TMP. ‘I’ve lost my identity’: on the mysteries of foreign accent syndrome. The MIT Press Reader. Some patients say they’ve also faced discrimination when speaking in public or being accused of faking their accents.

Psychologists play a part in the care team

“When a patient has developed FAS, psychologists can help treat them in a number of ways,” Bach says.

“This may involve helping them to develop new communication strategies or to understand and accept the changes to their speech. Additionally, psychologists can also provide support and guidance to patients as they navigate challenges such as social isolation or discrimination."

“By working with a psychologist, patients with FAS can receive the specialized care and support they need to manage their condition.”

Bach advises MDs who may work with a FAS patient to have compassion. “I believe that it is essential for medical professionals to be able to understand the unique challenges that patients with FAS face,” Bach says.

“I think that developing a supportive relationship with patients is key in helping them manage their condition.”

https://www.mdlinx.com/article/waking-up-with-an-irish-accent-foreign-accent-syndrome-piques-medical-curiosity/1CQt4t3H9DT8Uct1RJcYZY

Occult brain tumor

Our dear friend, Liza Burke, desperately needs our help. Liza, a senior at UGA, was enjoying her last spring break in Cabo San Lucas with a big group of friends. She woke Friday morning feeling great. At breakfast, she complained of a headache and went back to the room to rest. A few hours later, her friends called the doctor because they couldn't wake her. She was immediately rushed to the hospital where she was diagnosed with Arteriovenous malformation (AVM) which cause her brain to hemorrhage. She is currently on life-support. Her family and doctors are working hard to give her the best medical treatment possible. They have agreed that she needs to return to the U.S. immediately to receive expert care from experienced doctors. So many people have reached out wanting to help which is a testament to how many people Liza has touched. She is genuine, dynamic, playful and fierce. She has so much left to give to the world. Please continue to pray for her full recovery. All donations will help fund her life-flight transport from Mexico to Jacksonville. Thank you for loving our sweet Liza...

Liza suffered a brain hemorrhage while on Spring Break with friends in Mexico on Friday, March 10. She spent 3 nights in a small, private hospital in Cabo San Lucas, where her life was saved. Your contributions enabled her family to cover hospital costs for her care in Cabo San Lucas and her air ambulance travel to Jacksonville, Florida where she will receive the best medical care possible. Our strong girl is fighting, and we are slowly seeing signs of improvement as she can squeeze her mom’s hand, move her limbs slightly, and nod or shake her head in response to questions. We are still unsure of what lies ahead as there remain so many unknowns. Liza's care team is doing all they can to work towards the next steps...

A lot has changed since our last update. A very talented team of doctors have been working hard on our sweet Liza to get a firm diagnosis. We know now that is not AVM, but a brain tumor located near her brain stem. We had a successful biopsy yesterday and the pathology team is working to determine exactly what we are dealing with.

From Laura (mom)

10:30am update. It's Friday, the last day for action before the hospital goes dormant for 2 days. Dormant like this tumor likely was for many years before it became aggressive in a very short time. Thankfully, our optimistic Dr. Trifiletti (radiologist) is pushing her radiation mask through for today-even if they need to make it while she is still on the ventilator. We won't have a full pathology report for a week but he intends to start radiation on Monday as soon as the mask is ready. She'll get 30 sessions daily M-F over the next 5-6 weeks. There are potential side effects but well worth the risk given the rapid growth. Currently Liza is breathing on her own but until she responds to our commands (toe wiggle, hand squeeze) the doctors are reluctant to remove the vent. Please pray for her responsiveness and her fighting spirit. She's the leader in this fight but we are her warriors marching into battle with her...

Our strong Liza began radiation treatments yesterday, which will continue daily over the next six weeks. Her incredible medical team, including the wonderful Dr. Q, confirms that she is battling an aggressive brain tumor. Results from the brain biopsy, expected later this week, will allow them to further determine more specifics and adjust her treatment plan as needed. The family has decided to re-open the GoFundMe as costs associated with her care far exceed any medical coverage. We are extraordinarily grateful for your support and continued prayers for Liza’s recovery. As her mom, Laura, said, “Liza’s the leader in this fight but we are her warriors marching into battle with her.”...

"It is with both relief and belief that I share Liza’s passing at around 2:20 last night. Liza has now been reunited with her sister and they are making up for lost time!

Celebrations of Liza’s big energy are in the planning stages: one in Athens and another at a later date in her hometown of Asheville...

The family and friends of Liza thank you for your continued support of Liza through your thoughts, prayers and donations. At this time, we are closing the donations and ask that you consider donating to the Liza and Edie Burke Foundation. Please see details below.

Eliza (Liza) Grace Burke arrived right on schedule on July 10, 2001 and wasted no time living life to the fullest. She cherished her siblings, Jack and Edie. As her older sister’s abilities declined from the effects of MPS1, Liza proudly assumed the role of little “big sister” until Edie’s death when Liza was only six. Liza was the youngest of ten children born in her neighborhood in one calendar year and, although she was the smallest, she was the fiercest and the undisputed leader of the pack. She was open to wonder and magic, and was frequently found resting with her head on the family sofa and her feet in the air. She was steadfast in her love for family and friends (offering encouragement or a tiny shoulder to cry on), much like her abundant respect and care for animals (fostering and socializing limitless kittens) as well as the planet (recycle and stop wasting the AC, people!).

Liza lived large, like every day could be her last. She was not only at ease in nature, she was intrepid—whether watching sunsets from a mountain top tent, swimming solo across any body of water, or surfing in Central America. As Liza matured, she accomplished more in 21 years than many people do in a lifetime. She spoke two languages, played guitar, traveled the world, went skydiving, hiked across a glacier, joyfully sang and danced — always without fear of judgement. When she decided to go to the University of Georgia, she did so because others told her they LOVED it, not because of where its education might take her. It was the experience that mattered to Liza. She had an innate way of bringing people together, making everyone feel loved, and sharing her contagious laugh with those she met.


Astronomers have determined that the brightest, hottest, and most active stars have the shortest lifespans. Liza is like one of those brightest stars. In her short time here, she gave off an extraordinary amount of light, energy, and love. Her life serves a reminder to go through life unapologetically, take chances, speak and act boldly, cherish the little things, laugh often, and to stay present.

Following a six-week battle with a previously-undiagnosed brain tumor, Liza transitioned into the next realm peacefully while being cared for by friends and family. Heaven is undoubtedly rejoicing at her arrival. But she will be missed by so many in her hometown of Asheville, NC, and home-away-from-home, Athens, GA. Her survivors look forward to the day that Liza guides them from this lifetime into their next big adventure. They include her mother Laura McKeithen (Bryan Mickler); father Tom Burke; brother Jack Burke; and grandparents Loy McKeithen (Susan); Kitty McKeithen and Dennis Burke along with countless aunts, uncles, cousins, and friends across the globe.

https://www.gofundme.com/f/aeaet3-friends-of-liza-burke

See: 

A college student fell unconscious on Spring Break: Her story sheds light on a rare brain disorder 

https://www.mdlinx.com/article/a-college-student-fell-unconscious-on-spring-break-her-story-sheds-light-on-a-rare-brain-disorder/3Ny8cMqyJI5AT0tWsci7zB

Neurofibromatosis--mother and child

A Pennsylvania mother and her one-year-old son share an unusual bond. They are both living with the same rare genetic disease.

Lindsey Marson, 28, and her son, Bryson, were both born with Neurofibromatosis Type 1 (NF), "a genetic disorder that causes tumors to form throughout the body," according to Johns Hopkins Medicine.

The specific type of NF that Marson and her son have "is one of the most common inherited disorders and affects about one in every 3,000 people," the health care organization continued.

Even though the stay-at-home-mom and her baby have the same genetic disease, they are each impacted in different ways.

When Lindsey Marson was born, one of the hospital's nurses noticed several "light brown, flat patches" on her body — and indicated that this could be sign of NF, Marson told Fox News Digital.

As she continued to grow, her right leg started to curve into an "S" shape, called congenital pseudarthrosis of the tibia, another indicator of NF, she said. 

By the age of two, Marson was clinically diagnosed with NF Type 1.

Marson said that as a child, she had to have her leg lengthened and strengthened through an external fixation device, which ensures bones remain in an "optimal position during the healing process," according to the National Library of Medicine.

"I literally had 10 rods drilled through my bones. They came out through my skin, surrounded by a halo, and I had to turn pins each night that would separate the broken bone inside my leg," Marson said. 

"So that way new bone could grow, and my legs could catch up."

In spite of facing health challenges during her growing-up years, Marson was able to attend high school and even go on to beauty school before working at a hair salon for almost two years.

Being a hairdresser meant continuous standing. And even though Marson wears a brace full time, she found that long hours of sustained movement on her legs began to cause a great deal of pain, she said.

Marson left her salon and moved into a human resources position, which she said she loved because she calls herself a "people person."

"I wanted to change the dynamic of HR to employees or associates, because HR is always scary, and I never wanted to be the scary HR lady," Marson said.

"I wanted to be the one where people were like, ‘I can go to her for anything.'"

During her time in HR, Marson became pregnant with Bryson. Before that, she was doing research on genetic tests in the hope that he would not inherit the disease, she said.

"With NF, you have a 50% chance of passing along [the condition] to your child," Marson added.

Bryson was her "surprise blessing," as she likes to put it.

Marson said she chose to forgo any NF testing for her baby while she was pregnant, because she was planning on having the baby no matter the outcome.

One thing she learned along the way: NF presents itself differently for almost every person — even if people have the same type.

When Bryson was born, his eye was swollen and doctors at the time believed it was from birth trauma following her Caesarian section, Marson stated.

Shortly after giving birth, Marson took one-month-old Bryson to see an ophthalmologist, where he had an MRI.

"The MRI showed that he had a large plexiform tumor behind his eye, in his face and in part of his brain," Marson said.

By the time Bryson was three months old, the large tumor had grown — so he was taken to Children's Hospital of Philadelphia (CHOP) to start chemo.

He was put on MEK chemotherapy, an oral form of chemo that can administered at home.

While the chemo stabilized the tumor, side effects left Bryson with a severe rash — so Marson and Bryson's oncologist decided to stop administering the chemo, Marson said.

Surgery could not remove Bryson's tumor in its entirety because his particular tumor is "like a spider web throughout his face, his brain [and] his eye," Marson explained.

The tumor in Bryson's eye began compromising his vision, so a portion of the tumor was removed by his ophthalmologist.

Marson is now over a year old, but the tumors in his face and brain have only continued to grow, Marson said after her son had another MRI in May.

Marson and her son went through genetic testing, and it lined up perfectly. 

They "have the exact same variant," she stated — but they have completely different symptoms.

"I saw that NF could be severe, but I totally thought, 'I didn't have it severe, so Bryson is not going to have it severe,'" she added.

While seeing her son struggle with NF has been difficult, Marson said her own diagnosis of the same genetic disease has made it slightly easier because she has a level of understanding her own parents did not have when she was growing up.

"We are definitely closer because of this. I mean, he is my little baby."

"It was still really scary, and I still felt extremely guilty," Marson said.

She added, "It was still hard, but it wasn't as hard because I knew all the terminology and I knew what to expect."

Marson believes the best thing a parent can do for a child is be an advocate — and find moments of positivity.

She started a Facebook page to educate others on the condition, hoping to bring awareness to NF and help others know how to recognize it in a child.

"We are definitely closer because of this. I mean, he is my little baby," Marson said of herself and her son.

"I feel like we have a stronger bond because of it and I know what he is going through, and I will be there for him 100% of the time," she said. 

This year, the Children's Tumor Foundation featured Marson and Bryson in a photo series with other parents and their children who are fighting NF together.

https://www.foxnews.com/lifestyle/pennsylvania-mother-son-both-born-rare-genetic-disease-closer-this

The study and use of psychedelics in cluster headache

Headache Horizons: The Study and Use of Psychedelics in Cluster Headache

Psychedelics have a history of use in headache disorders and evidence exists for their therapeutic benefit in cluster headache.

Risako A. Shirane, MD, MSc; Christopher H. Gottschalk, MD, FAHS; and Emmanuelle A.D. Schindler, MD, PhD, FAHS

Cluster headache (CH) is a rare primary headache disorder characterized by paroxysmal attacks of unilateral severe orbital or periorbital pain. Also known as suicide headache, CH is said to be the most intensely painful condition known to humankind. CH affects up to 0.1% of the population, with a significant male predominance. CH refers to the disorder; cluster attacks, to the paroxysms of head pain. People with episodic CH have pain attacks during cluster periods or cycles, which last from weeks to months. People with chronic CH have attacks year-round without a remission period (an extended attack-free period) for longer than 3 months. Cluster attacks occur up to 8 times per day, each lasting for 15 to 180 minutes. Because of its severity and propensity to occur overnight, CH has deleterious effects on sleep, as well as quality of life overall.

Abortive treatment in CH involves the inhalation of high-flow oxygen or use of parenteral triptan medication. The newest abortive therapy is noninvasive vagus nerve stimulation (gammaCore; electroCore, Rockaway, NJ). Preventive treatment, which suppresses attacks during cycles or in chronic CH, has included such medications as verapamil and lithium. The noninvasive vagus nerve stimulation device also can be used in preventive treatment, as can galcanezumab (Emgality; Eli Lilly, Indianapolis, IN), a monoclonal antibody against calcitonin gene-related peptide, for treatment of episodic CH. Transitional treatments in CH are short-term interventions that serve to suppress attack frequency or intensity, shorten cluster cycles, or induce temporary remission in chronic CH. Such treatments include pulse regimens with corticosteroid or dihydroergotamine, or anesthetic nerve blockade of occipital nerves or the sphenopalatine ganglion.

Whereas treatment options in CH have increased in recent years, their use often is limited by poor accessibility, low tolerability, or medical contraindications. Therefore, there is an ongoing need to identify other treatment options for CH. Emerging data suggest that psychedelic drugs possess therapeutic potential and do so in a novel way. In this brief narrative review, we explore the history of psychedelics in headache medicine and the existing evidence on their therapeutic benefits for CH.

Definition of a Psychedelic

In this review, we discuss classic psychedelics, which are a group of 5-hydoxytryptamine (5-HT) 2A receptor agonists that produce acute alterations in sensation, perception, mood, and consciousness. The most well-known classic psychedelics include psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and mescaline. Reports of therapeutic benefits of psychedelic drugs exist for several neuropsychiatric disorders, including depression, obsessive-compulsive disorder, and substance use disorders, as well as chronic pain disorders. Unlike conventional medications, psychedelics show long-lasting (ie, months) therapeutic effects after limited dosing (ie, 1 to 3 doses) based on existing clinical reports. However, because of their acute intoxicating effects and associated regulatory concerns, psychedelics are not available for routine clinical use.

Drugs such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also produce acute psychedelic-like effects; however, they are not classic psychedelics, because of their distinct pharmacology. Although ketamine has been suggested to have abortive effects in CH,4 the effects do not appear to be long-lasting after limited dosing, as occurs with the classic psychedelics. MDMA does not appear to have beneficial effects in CH. One survey study suggested that MDMA extended the duration of a CH attack.

History of Psychedelics in Headache Medicine

Albert Hofmann, a Swiss chemist, created LSD in 1938 while seeking to identify a bronchoconstrictive and vasoconstrictive medicine. He first discovered the psychedelic effects of LSD in 1943 and later isolated psilocybin from Psilocybe mushrooms. Psychedelics were first investigated as treatments for headache disorders more than 60 years ago. Several medications routinely used in headache management share chemical or pharmacologic properties with psychedelic drugs. For example, triptans, dihydroergotamine (DHE), and methylsergide are all serotonergic compounds that share an indolamine structure with psilocybin, LSD, and DMT.

Scientific inquiry into the effects of psychedelics on CH remains limited, but a global community of people with CH has led the research initiative by sharing their experiences. The first documentation of disease self-management with a psychedelic was reported by an individual with episodic CH in the late 1990s, who posted on a CH website message board (https://clusterheadaches.com) about therapeutic effects after ingestion of LSD (which was taken for recreational purposes). Despite initial resistance, reports of success using LSD and psilocybin mushrooms in CH spread among the CH community. Now, scientists are studying these patient-informed treatment regimens; controlled studies on the safety and therapeutic effects of psychedelics are starting to emerge.

Descriptive Studies

What appears to set psychedelics apart from other headache medicines is their reported ability to produce lasting therapeutic effects after small, limited doses (1 to 3). This is in stark contrast with conventional medications that are dosed daily (sometimes lifelong), and take weeks or months for the desired effects, and maximal effects, to occur. Although psychedelics have also been reported to abort CH attacks,7,8 given the short duration and high frequency of attacks in the disorder, this method of treatment is not practical.

Several descriptive studies have supported the ability of psychedelics to induce and prolong remission periods with limited administration of low doses and subhallucinogenic doses7-11. A small survey of people with CH in 2006 showed that 88% and 52% of respondents found LSD and psilocybin to be effective preventive agents, respectively. A more recent online survey of nearly 500 people with CH showed that psilocybin, LSD, and lysergic acid amide (LSA; a psychedelic found in morning glory seeds) were significantly more effective than verapamil and prednisone in preventing CH attacks. A review of CH survey studies identified consistency among reports of psilocybin and LSD preventive effectiveness. Psilocybin is the most commonly tried psychedelic in these surveys11 and individuals reported dosing from every few weeks to twice annually. Low and subpsychedelic doses of LSD and psilocybin are reported to be used, and in a case series, a nonhallucinogenic congener of LSD, 2-bromo-LSD (BOL-148), was also shown to break a CH cycle, reduce attack frequency and intensity, and induce remission.

Clinical Trials

Some small controlled clinical trials have evaluated the safety and efficacy of psilocybin. Studies of LSD in CH are ongoing or in preparation. The first randomized controlled study of psilocybin in CH13 used a patient-informed, low-dose pulse regimen and demonstrated safety of psilocybin with no unexpected or serious adverse events. The weekly attack frequency was moderately reduced in the experimental group in the first 3 weeks, and this was particularly notable among individuals with chronic CH. The change in attack frequency was not statistically significant (P=.251), likely because of the small sample size. The researchers also observed separation of therapeutic and acute psychotropic effects. An extension phase of this study has completed and will begin to inform on the safety and efficacy of repeating the psilocybin pulse regimen (Psilocybin for the Treatment of Cluster Headache, NCT02981173). A study with an open-label design, EPOCH (Prophylactic Effects of Psilocybin on Chronic Cluster Headache, NCT04280055), investigating the effects of the same low-dose psilocybin pulse in chronic CH showed that the treatment was safe, was well-tolerated, and reduced attack frequency by 30% (P=.008) (Table 2).

The small number of participants in each study limits reliability and generalizability of the findings. Even with ongoing work, differences in dosing regimens and outcomes among studies will limit the consolidation of findings. Larger, more representative trials are required, although there are unique logistic and methodologic challenges associated with both CH and psychedelic trials, including recruitment difficulty because of rarity of the disease, timing of drug administration in episodic cases, and controlling for comorbidities and polypharmacy.

Whereas the acute psychedelic effects are believed to be relevant in the therapeutic use of psychedelics in psychiatric disease, research of psilocybin in CH and migraine has demonstrated that the transitional therapeutic effects are independent of the psychedelic effects.13,15 This along with reports of the use of low and subpsychedelic doses by people with CH7,8 and the therapeutic effects of the nonpsychedelic compound BOL-148 in CH12 urge the consideration of an alternate mechanism of action. Researchers in the open-label EPOCH study performed functional MRI before and after psilocybin administration and found involvement of hypothalamic–diencephalic functional connectivity in treatment response.14 The relationship of treatment response to circadian and sleep systems is also being investigated in the Psilocybin for the Treatment of Cluster Headache clinical trial.

Conclusion

Psychedelics have emerged as a potential therapeutic drug class for CH. Their beneficial effects have been reported for decades, although the existing data from clinical trials are far from conclusive and must be interpreted with caution. Continued research on psychedelics is warranted, particularly as psychedelics may also offer a means to understand the pathogenesis of CH.

https://practicalneurology.com/articles/2023-aug/headache-horizons-the-study-and-use-of-psychedelics-in-cluster-headache