Sunday, July 30, 2023

Safety of diazepam nasal spray in pediatric patients with developmental epileptic encephalopathies

Tarquinio D, Wheless JW, Segal EB, Misra SN, Rabinowicz AL, Carrazana E. Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study. Journal of Child Neurology. 2023;0(0). doi:10.1177/08830738231185424


Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients ( NCT02721069).

The efficacy and safety of rituximab for the treatment of pediatric autoimmune neuroinflammatory disorders

Ko YJ, Shim YK, Kim WJ, Kim SY, Kim H, Hwang H, Chae JH, Choi JE, Kim KJ, Lim BC. The Efficacy and Safety of Rituximab for the Treatment of Pediatric Autoimmune Neuroinflammatory Disorders at a Single Center. Ann Child Neurol. 2020;28(1):30-36.


Rituximab is increasingly used as a second-line treatment of neuroinflammatory disorders to improve clinical outcomes in cases refractory to conventional immunotherapy and to reduce relapses. This study aimed to demonstrate the efficacy and safety of rituximab used for pediatric autoimmune neuroinflammatory disorders.

We retrospectively reviewed the medical records of 32 patients (median age, 8.5 years; range, 1.1 to 17.1; 23 girls) who received rituximab treatment at Seoul National University Children’s Hospital. The disease subgroups were anti-N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis (n=11), opsoclonus-myoclonus ataxia syndrome (OMAS) (n=10), other suspected autoimmune encephalitis (n=5), neuromyelitis optica spectrum disorder (n=4), and chronic inflammatory demyelinating polyneuropathy (n=2). Efficacy was measured by modified Rankin Scale (mRS) scores at the initiation of rituximab administration, at 2 months after initiation, and at the last follow-up. A favorable clinical outcome was defined as an improvement of ≥2 in the mRS score or achievement of an mRS score ≤2. Safety was assessed by reviewing infusion-related adverse events and infectious complications, including progressive multifocal leukoencephalopathy.

Two months after the initiation of rituximab therapy, 21patients (65.6%) had a favorable response, while 26 (82.1%) had a favorable response at the last follow-up. Among the disease subgroups, anti-NMDAR encephalitis and OMAS showed especially good responses. Rituximab infusion-related adverse events were identified in nine patients (28.1%). All complications recovered spontaneously or with only symptomatic treatment.

Rituximab can be used safely for various pediatric autoimmune neuroinflammatory diseases. Rituximab is expected to improve clinical outcomes in pediatric patients with anti-NMDAR encephalitis and OMAS.

Tuesday, July 25, 2023

Real-life efficacy and tolerability of lacosamide in pediatric patients

Shin Yun Byun, Juhyun Kong, Soo Young Lyu, Sang Ook Nam, Young Mi Kim, Gyu Min Yeon, Yun-Jin Lee. Real-Life Efficacy and Tolerability of Lacosamide in Pediatric Patients Aged 4 Years or Older with Drug-Resistant Epilepsy. Annals of Child Neurology 2023;31(3):206-214. Published online: June 20, 2023 DOI:


The aim of this study was to evaluate the efficacy and safety of adjunctive lacosamide therapy in pediatric patients aged ≥4 years with drug-resistant epilepsy (DRE).

Medical records of children aged 4 to 19 years treated with lacosamide as adjunctive therapy for DRE were retrospectively reviewed. The patients were divided into two groups according to their age at the start of lacosamide treatment: group A (aged 4-15 years) and group B (aged 16-19 years). Changes in seizure frequency from baseline, adverse events, and the retention rate were evaluated at each follow-up visit.

Sixty-two patients (33 males and 29 females) with a mean age of 11.4 years (range, 4 to 19) were included. The mean duration of follow-up was 20.1±12.9 months. The mean maintenance dose of lacosamide was 6.7±4.8 mg/kg/day. Forty-two patients (67.7%) were responders (≥50% reduction in seizures) with 19.4% (12/62) achieving freedom from seizures. The response rate did not differ significantly between groups A and B (67.6% vs. 68.0%, P=0.795) and was not affected by the concomitant use of sodium channel blockers. Significant independent factors associated with a good response to lacosamide treatment were a shorter duration of epilepsy (P=0.035) and fewer concomitant anti-seizure medications (P=0.002). Mild transient adverse events were observed in 20 patients (32.3%).

Lacosamide adjunctive therapy was efficacious and tolerated in children aged ≥4 years with DRE. Early use of lacosamide may be helpful for a good response to drug-resistant seizures.

Sunday, July 23, 2023

Medical child abuse revisited 6

Police arrested Kasumi Nawata a Japanese woman in Osaka, Japan, for allegedly starving and abusing her eight-year-old daughter to hospitalize her and fraudulently claim insurance payments.

The girl's mother is suspected of telling her daughter not to eat and feeding her laxatives. The alleged forced starvation and malnutrition are suspected to have led to the daughter developing ketotic hypoglycemia so that she could be hospitalized. Daito City officials said that Nawata told the school that her daughter has an intractable disease and needed to be hospitalized regularly to have tests done, according to Yahoo! News Japan.

However, after police contacted the medical institutions they found no proof that the daughter had ever been diagnosed with such a disease. Police suspect that the mother told the school this so that they would not infer abuse.

The Japan Times report stated that investigators believed that the mother regularly starved her daughter, hospitalizing her 43 times for a total of 332 days since spring 2018 and subsequently obtaining some $40,000 in insurance benefits from three institutions.

Prefectural police had previously arrested Nawata three times between March and June, leading to two indictments "on suspicion of causing her daughter to have hypoglycemia, forcing her daughter to take laxatives and causing bodily harm."

Alarms were raised when the daughter was hospitalized earlier in February a nurse overheard a conversation between the daughter and her mother.

According to Yahoo! News Japan, Nawata, frustrated with her daughter, reportedly told her "Don’t eat! Just go to sleep!" Admonishing her daughter, Nawata said.

The incident at the hospital helped lead to subsequent police investigations of Nawata. However, there was another incident from October of 2022 that was overlooked by child welfare officials and not reported to law enforcement.

Fuji News Network (FNN) reported that Daito City Hall received an anonymous tip suspecting abuse in October 2022, which led to Nawata’s first arrest. The informant presumed that the constant hospitalization was due to the mother not giving adequate food to her daughter.

Kazuhisa Takahashi, deputy director and manager of the Office for Children and Families, Welfare and Children Department at Daito City Hall, told Fuji News Network that he believed his agency's response "was appropriate." The day after the first anonymous tip, the department reported the concern to the child’s school.

"Authorities acted slowly and inappropriately," Viktoriya Shirota, who served as director of NPO Michel Club, which helps serve disadvantaged families in Japan, told Fox News Digital. Shirota assisted Japanese child welfare services with cases of domestic violence. Shirota noted that officials in charge of caring for children and spotting domestic abuse need proper training and that legislation needs to be changed.

"Japan does not have joint custody and has a strict policy over family units, so it’s quite difficult to take a child away from an abusive parent, especially if it’s a single-mother case."

On February 9, Nawata’s daughter was placed under the care of child protective services, where police and Daito City report that she is eating three meals a day and healthy.

Nawata denied the allegations against her, telling Japanese media that she had not deliberately caused her daughter to suffer and nor had she tried to fraudulently take money that had been meant for the child from the insurance company. 

Why Stanford President Marc Tessier-Lavigne resigned

Stanford President Marc Tessier-Lavigne, who will step down from his position Aug. 31, was initially accused of scientific misconduct, but that’s not why he lost his job. He lost it because he failed to adequately lead his labs, and because of the repercussions that failure had for his leadership of a premier research institution. In his own words, Tessier-Lavigne resigned because Stanford “needs a president whose leadership is not hampered” by discussions of problems with his own research. As someone who studies and instructs graduate students on the responsible conduct of research, I am encouraged by what I see in this case as a step towards expecting more from researchers.

A prominent person’s fall from grace often signals a healthy environment able to identify and address threats. Mark Tessier-Lavigne’s resignation suggests that leaders may now be held more accountable for meeting standards of research integrity that go beyond merely not lying about their work. Ultimately, his resignation may signal — or establish — higher public expectations for research integrity and encourage us to build structures to support them.

By the usual metrics of funding, publications, and recognition, Tessier-Levigne was clearly a leader in his field. But the panel investigating the accusations was tasked with assessing his “approach to correcting issues or errors in the scientific record” and his “management and oversight of his scientific laboratories.” They concluded that he “failed to decisively and forthrightly correct mistakes in the scientific record.” Moreover, they noted that given the “unusual frequency of manipulation and/or substandard scientific practices” in his labs across many years and different locations, “there may have been opportunities to improve laboratory oversight and management.”

To put it simply, he failed to foster a culture of research integrity and model it for his trainees and collaborators by confronting allegations quickly and openly.

Tessier-Levigne’s resignation is an unusual consequence of accusations of research misconduct. The closest example of this kind of consequence for an academic leader may be Terry Magnuson, former vice chancellor for research at the University of North Carolina at Chapel Hill, who resigned in 2022 after admitting to plagiarism in federal grant applications.

However, Magnuson’s actions fit the standard federal policy definition of research misconduct, defined narrowly as encompassing only fabrication, falsification, and plagiarism. When someone is accused of and found to have committed misconduct, possible consequences include employment termination, debarment from grant funding, or even civil liability. When found not to have committed misconduct, they typically return to their previous life.

Thus, one might have expected Tessier-Lavigne to be in the clear with the report’s conclusion that there is no evidence he committed misconduct or clearly knew about misconduct in his labs. Instead, he lost his job for behavior that has up until this point not typically been subject to consequences.

For instance, it seems that there was pressure for researchers in Tessier-Levigne’s lab to perform — but not unusually so. One of Tessier-Lavigne’s former postdocs told STAT, “I would say categorically that I think there was no more pressure in Marc’s lab than a lot of other labs.” Stories of toxic lab cultures, competitive researchers, and intense pressure for results that lead to grant funding and publications are widespread. This does not excuse his failure to address numerous questions about his research over the years, or what some reporting described as his preferential treatment of students who had results. As STAT reported previously, an anonymous former student observed, “When you didn’t please him, you didn’t get any attention.” But there have been consequences for him, and this is the most conspicuous recent example of a high-profile researcher bearing the consequences of failing to prevent such a culture.

Exacerbating these issues of research culture is the challenge of assigning responsibility in multi-author publications. Modern research is more expensive, interdisciplinary, international, and collaborative than it has been historically, with the consequence that the number of authors on publications has proliferated. It is unrealistic to think that one person can adequately oversee all work in a project. But if no individual actually can be completely responsible, isn’t everyone off the hook?

In many research collaborations, not all authors see raw data. That happens for many good reasons — for example they might they lack appropriate training to understand it, or the data include identifying details limiting who may view them.

But for science to work, someone must accept that responsibility. In his resignation letter, Tessier-Levigne endorsed this expectation: “Although I was unaware of these issues, I want to be clear that I take responsibility for the work of my lab members.”

Leaders are the only people in a research project who can create a microclimate that supports rigorous, honest research. This includes: cultivating a research culture in which expectations for scientific rigor and ethical action are clear and supported; being open, transparent, and responsive when problems arise; and otherwise modeling high standards in research. Tessier-Lavigne failed to do this, and if the panel had found otherwise, he might not have needed to resign.

But individuals alone can only do so much. Knowing that humans are fallible, imperfect, and prone to temptation, we should also create and support good practices with institutional, disciplinary, and national structures to foster research integrity.

In some ways, this is a story about how such structures, built in the past decade or so precisely to improve scientific rigor, helped to identify and draw attention to cases like this. For example, PubPeer, where the problems with Tessier-Levigne’s research were initially identified, was created “to improve the quality of scientific research by enabling innovative approaches for community interaction.” Data sleuths have taken it upon themselves to support good science by calling out problematic practices, and the Open Science movement makes it easier to identify problematic data, methods, or conclusions.

But these grassroots efforts are not enough. Even the toppling of a high-profile researcher does little to support structural change, and in fact can misdirect our focus to only individual solutions. For years there have been calls for data auditing at the institutional level, less focus on the metrics that reduce a researcher’s success to dollars or citations, training in good practices of mentoring, and the creation of a federal research integrity agency. These would be excellent steps toward publicly emphasizing the importance of research integrity and assigning responsibility to institutions to do more to support it.

This case emphasizes the importance of both individual and institutional efforts to improve research rigor and reliability. When looking for leaders, we should seek and select not only those with the most research funding or highest citation counts, but also those who know how to foster an ethical research culture, including rapidly and transparently addressing anything that might affect research integrity. At the same time, because we can’t reasonably expect that all researchers will behave optimally, we must consider structural tools to foster research integrity.

Thursday, July 20, 2023

Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy

New results from the NURTURE (NCT02386553) clinical trial, published in Muscle & Nerve, indicate that treatment of children with genetically diagnosed but presymptomatic spinal muscular atrophy (SMA) using Spinraza (nusinersen; Biogen, Cambridge, MA) was effective and helped preserve motor function long term. Analysis of results also provides novel insights into early markers of SMA disease progression before the onset of symptoms.

NURTURE is an open-label study examining the efficacy of Spinraza for the treatment of children with genetically diagnosed but presymptomatic SMA. The study includes 25 participants no older than 6 weeks who have multiple copies of survival motor neuron 2 (SMN2). The primary endpoint is time to death or respiratory intervention, with secondary outcomes assessing growth, World Health Organization (WHO) motor milestones, adverse events, and laboratory parameters. After the initial 3-year analysis, participants showed improvements in secondary outcomes.

Data reported in Muscle & Nerve from an additional 2-year follow up period revealed that all 25 participants were still alive, and none discontinued treatment. Nine of the 10 participants with 3 SMN2 copies achieved WHO motor milestones within age-appropriate timelines, with 1 participant walking with assistance late, but then meeting the timeline for walking alone. All participants with 2 SMN2 copies sat without support, 14/15 achieved walking with assistance, and 13/15 walked alone. Overall, 23 of the 25 participants were able to walk after 5 years of treatment. Additionally, researchers identified that the subgroup of participants with 2 SMN2 copies, excluding those with a compound muscle action potential (CMAP) no less than 2 mV or with areflexia, showed better outcomes than the rest of the cohort.

“The NURTURE data show how small differences in baseline characteristics can greatly impact outcomes, including motor function, respiratory function, swallowing and feeding,” said Thomas Crawford, MD, Codirector of the Muscular Dystrophy Association Clinic.

SMA is a rare neuromuscular disorder characterized by progressive muscle weakness due to loss of motor neurons that affects approximately 1 out of every 10,000 people in the United States. It is the most common genetic cause of infant death.

Crawford TO, Swoboda KJ, De Vivo DC, Bertini E, Hwu WL, Finkel RS, Kirschner J, Kuntz NL, Nazario AN, Parsons JA, Pechmann A, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Zhu C, Raynaud S, Lago TR, Paradis AD, Foster R, Chin R, Berger Z; NURTURE Study Group. Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5-year update of the NURTURE study. Muscle Nerve. 2023 Aug;68(2):157-170. doi: 10.1002/mus.27853. Epub 2023 Jul 6. PMID: 37409780.


Introduction/aims: NURTURE (NCT02386553) is an open-label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow-up (data cut: February 15, 2021) are reported.

Methods: The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety.

Results: Median age of children was 4.9 (3.8-5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies.

Discussion: These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

Tuesday, July 18, 2023

Neonatal hyperammonemia and cerebellar hemorrhages

This 36-week gestation baby was transferred from another hospital because of metabolic acidosis, respiratory distress, and abnormal movements. His mother’s pregnancy was complicated by maternal diabetes, premature rupture of membranes, and a three-day history of vaginal bleeding. He was born limp, lethargic, and cyanotic, with Apgar scores of 3 and 7 at one and five minutes. On day two of life, he developed metabolic acidosis and required intubation because of apnea. He exhibited abnormal facial movements and posturing that were suspected to represent seizures.

Phenobarbital and levetiracetam were halted after continuous electroencephalography showed no epileptiform discharges during the abnormal movements. Blood cultures and cerebrospinal fluid analysis were unremarkable aside from the spinal fluid protein of 240 mg/dL. An inborn error of metabolism was initially suspected because his serum ammonia was dramatically elevated at 1284 μg/dL. Urine organic acids, plasma amino acids, serum pyruvate, and carnitine were normal. However, next-generation DNA sequencing of serum confirmed evidence of Ureaplasma urealyticum, and he began azithromycin.

His hospital course was complicated and prolonged. His ammonia level increased to 1374 μg/dL despite infusion of sodium benzoate and sodium phenylacetate, and he began continuous kidney replacement therapy. At one week of age, he was documented to have multifocal cerebellar hemorrhages on ultrasound and computed tomography. He developed a thrombosis of the right external iliac and right common femoral veins and was anticoagulated with careful monitoring of the cerebellar hemorrhages. By three weeks of age, his condition had improved and his ammonia level had fallen to 63 μg/dL.

What caused this child’s hyperammonemia? Why did he develop cerebellar hemorrhages?

This child was first suspected to have seizures, but continuous electroencephalography showed no epileptiform discharges even during the movements. His serum ammonia level was dramatically elevated, but subsequent testing failed to identify an inborn error of metabolism. The cause of his hyperammonemia was quickly clarified by the presence of Ureaplasma urealyticum. These organisms release substantial amounts of ammonia during urea hydrolysis, sometimes leading to clinical hyperammonemia.1,2

The reason for the multifocal cerebellar hemorrhages is less certain. Cerebellar hemorrhages have been documented in children with organic acidemias.3-5 Propionic, methylmalonic, and isovaleric acidemia typically present in babies as acute metabolic decompensation and encephalopathy, often associated with hyperammonemia. We suspect that severe hyperammonemia, whatever its origin, may promote cerebellar hemorrhage in neonates. However, most of these children are seriously ill, so it is possible that other factors could be responsible.

When seen at 13 months of age, the child was thriving. He had experienced no seizures or periods of lethargy. He was starting to walk, playfully interacting, and saying several typical words.

Final Diagnosis

(1) Severe hyperammonemia due to Ureaplasma urealyticum sepsis and (2) bilateral cerebellar hemorrhages, possibly related to hyperammonemia.


Cheema F, Kutzler HL, Olowofela AS, et al. Successful management of noncirrhotic hyperammonemia syndrome after kidney transplantation from putative Ureaplasma infection. Transpl Infect Dis 2020;22:e13332.

Higgins AB, Farmakiotis D, Rogers R, et al. Hyperammonemia syndrome due to Ureaplasma urealyticum in a kidney transplant recipient: a case of disseminated disease from a fluoroquinolone-resistant isolate. Transpl Infect Dis 2020;22:e13328.

Dave P, Curless RG, Steinman L. Cerebellar hemorrhage complicating methylmalonic and propionic acidemia. Arch Neurol 1984;41:1293-1296.

Velasco-Sanchez D, Gomez-Lopez L, Vilaseca MA, et al. Cerebellar hemorrhage in a patient with propionic acidemia. Cerebellum 2009;8:352-354.

Fischer AQ, Challa VR, Burton BK, McLean WT. Cerebellar hemorrhage complicating isovaleric acidemia: a case report. Neurology 1981;31:746-748.

Thursday, July 13, 2023

Disease course in multiple sulfatase deficiency differs from metachromatic leukodystrophy

Beck-Wödl S, Kehrer C, Harzer K, Haack TB, Bürger F, Haas D, Rieß A, Groeschel S, Krägeloh-Mann I, Böhringer J. Long-term disease course of two patients with multiple sulfatase deficiency differs from metachromatic leukodystrophy in a broad cohort. JIMD Rep. 2020 Dec 8;58(1):80-88. doi: 10.1002/jmd2.12189. PMID: 33728250; PMCID: PMC7932862


Multiple sulfatase deficiency (MSD) is a lysosomal storage disease caused by a deficiency of formylglycine-generating enzyme due to SUMF1 defects. MSD may be misdiagnosed as metachromatic leukodystrophy (MLD), as neurological and neuroimaging findings are similar, and arylsulfatase A (ARSA) deficiency and enhanced urinary sulfatide excretion may also occur. While ARSA deficiency seems a cause for neurological symptoms and later neurodegenerative disease course, deficiency of other sulfatases results in clinical features such as dysmorphism, dysostosis, or ichthyosis. We report on a girl and a boy of the same origin presenting with severe ARSA deficiency and neurological and neuroimaging features compatible with MLD. However, exome sequencing revealed not yet described homozygosity of the missense variant c.529G > C, p.Ala177Pro in SUMF1. We asked whether dynamics of disease course differs between MSD and MLD. Comparison to a cohort of 59 MLD patients revealed different disease course concerning onset and disease progression in both MSD patients. The MSD patients showed first gross motor symptoms earlier than most patients with juvenile MLD (<10th percentile of Gross-Motor-Function in MLD [GMFC-MLD] 1). However, subsequent motor decline was more protracted (75th and 90th percentile of GMFC-MLD 2 (loss of independent walking) and 75th percentile of GMFC-MLD 5 (loss of any locomotion)). Language decline started clearly after 50th percentile of juvenile MLD and progressed rapidly. Thus, dynamics of disease course may be a further clue for the characterization of MSD. These data may contribute to knowledge of natural course of ultra-rare MSD and be relevant for counseling and therapy.

Internal decapitation 3

Surgeons in Israel performed a miracle surgery and managed to reattach a boy’s head after he was hit by a car while riding his bike, the Jerusalem hospital announced this week.

Suleiman Hassan, a 12-year-old Palestinian from the West Bank, suffered what is known as an internal decapitation, with his skull detached from the top vertebrae of his spine – officially known as a bilateral atlanto occipital joint dislocation, according to The Times of Israel. 

He was riding his bike when a car hit him. The boy was rushed to Hadassah Medical Center and immediately put him into surgery in the trauma unit. The doctors said his head was "almost completely detached from the base of his neck."

Dr. Ohad Einav, the orthopedic specialist who led the operation, said the procedure took several hours and required the doctors to use "new plates and fixations in the damaged area." 

"Our ability to save the child was thanks to our knowledge and the most innovative technology in the operating room," Einav said, adding that the team "fought for the boy’s life." 

Einav and his team said that Hassan has a projected survival rate of only 50%, and his recovery is nothing short of a miracle, according to i24 News. 

The operation occurred in June, but doctors waited a month to announce the results. The hospital recently discharged Hassan with a cervical splint and will continue to monitor his recovery. 

"The fact that such a child has no neurological deficits or sensory or motor dysfunction and that he is functioning normally and walking without an aid after such a long process is no small thing," Einav said.

According to Israel's TPS news agency, Hassan’s father did not leave his son’s bedside during the recovery process, saying he had nothing but a "big thank you" for the medical staff. 

"Bless you all," the father said. "Thanks to you, he regained his life even when the odds were low and the danger was obvious."

"What saved him were professionalism, technology and quick decision-making by the trauma and orthopedics team," TPS reported the father as saying. 

Dr. Marc Siegel, Clinical Professor of Medicine and a practicing internist at NYU Langone Medical Center and Fox News contributor, told Fox News Digital that the "amazing" surgery was only possible if major blood vessels remained intact. "The key is preserving blood flow to the brain," Siegel said. "It sounds like - from the story - that the major blood vessels were likely not severed and that this involved an orthopedic rebuilding - probably using rods and reattaching ligaments and possibly bone grafts and implants."

Einav stressed that the surgery is "extremely rare," but the large size of a child’s head relative to an adult means they are "more susceptible."

"This is not a common surgery at all, and especially not on children and teens. A surgeon needs knowledge and experience to do this," he said.


Intravenous ketamine for pediatric refractory headaches

Key takeaways:
Researchers conducted a retrospective chart review of 58 encounters of 38 pediatric patients with refractory headache.
Treatment with IV ketamine led to 50% pain reduction at discharge.

Treatment with IV ketamine for pediatric refractory headache resulted in a 50% reduction in pain at discharge, with nearly two-thirds of patients not requiring rescue care within 1 month, according to a poster presentation.

“Patients with severe and refractory headaches often have few options for treatment despite ongoing pain and significant disability,” Scott Rosenthal, MD, a child neurology resident in the department of pediatrics at University of Colorado Anschutz Medical Campus, and colleagues wrote. “Ketamine has emerged as a potential therapeutic option and had demonstrated benefit in other chronic pain syndromes.”

Researchers conducted a retrospective chart review of 58 encounters of 38 patients aged 5 to 21 years (median age, 15.8 years; 76% girls) who were admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of refractory headache with continuous IV ketamine.

The primary outcome was percent pain reduction at discharge compared with baseline, headache recurrence within 72 hours, headache recurrence within 30 days of discharge, side effects of medication and serious adverse events.

According to results, treatment resulted in a 50% median pain reduction at discharge, with 64% of patients reporting no headache recurrence within 1 month of hospital discharge.

Among patients with recurrence, median time was 7 days, with 9% experiencing recurrence within 72 hours.

While no serious adverse events were reported, 7% of encounters stopped treatment because of side effects.

“Intravenous ketamine is an effective, safe and well-tolerated treatment option for refractory pediatric headaches and status migrainosus,” Rosenthal and colleagues wrote.

Conferences|American Headache Society Annual Scientific Meeting
The use of intravenous ketamine in pediatric patients with refractory headaches resulted in a median pain reduction of 50% at discharge and nearly two-third of patients did not need further rescue therapies 1 month posttreatment.

Findings from a recent study of pediatric patients with refractory migraine demonstrated a significant reduction in pain at discharge using intravenous ketamine as a treatment with no serious adverse events. These results suggest that intravenous ketamine is an effective, safe, and well-tolerated option for treating refractory pediatric headaches and status migrainosus.

All told, the median percent pain reduction at discharge was 50% (IQR -67% to +25%) among 58 encounters with pediatric patients with refractory migraine. Of note, 64% of patients did not have headache recurrence or exacerbation in 1 month after discharge. Notably, the median time to recurrence was 7 days (IQR, 3-12.5) for those that recurred and 9% had recurrence in 72 hours postdischarge.

"Patients with severe and refractory headaches often have few options for treatment despite ongoing pain and significant disability. While intravenous dihydroergotamine (IV DHE), an ergot derivative with 5HT agonism, is often effective for the majority of pediatric patients presenting with status migrainosus and refractory headaches, a significant proportion of patients will fail to respond or cannot receive IV DHE due to intolerability/contraindications," lead author Scott Rosenthal, MD, a child neurology resident at Children's Hospital Colorado, University of Colorado School of Medicine and colleagues wrote.1

Presented at the 2023 American Headache Society (AHS) Annual Meeting, June 15-18, in Austin, Texas, researchers conducted a retrospective chart review of patients between the ages of 5 and 21 years old. To be eligible, the patients had to be admitted to a tertiary pediatric referral center for the treatment of refractory headache. Patients were excluded if they received both ketamine and IV dihydroergotamine (DHE) in the same period, had a secondary etiology for headache, or had a pain score that was less than 3 on a verbal analogue scale at presentation.

Investigators used the percentage of pain reduction at discharge ([Discharge Pain Score - Initial Pain Score]/Initial Pain Score*100) as the primary outcome, while also observing serious adverse events, medication adverse effects, headache recurrence in 72 hours, and headache recurrence in 30 days postdischarge. Investigators defined headache recurrence if patients made a phone call or representation of care for headache requiring rescue therapy. Demographic variables from the patients were also collected.

In the analysis, 58 encounters comprised of 38 unique pediatric patients with a median age of 15.8 years (IQR 13.42-17.41), 76% of which identified as women, were included. Seventy-eight percent of patients were diagnosed as chronic migraine without aura and he median duration of headache or headache pain exacerbation at presentation was 10 days (IQR, 3-26.5). Also, the median maximum dose of intravenous ketamine was 0.28 mg/kg/hour (IQR, 0.2-0.4), with the median duration of infusion being 3 days (IQR, 2-3).

Although there were no serious adverse events reported in the analysis, the most common adverse effects were dizziness (19%), nausea (12%), hallucinations (12%), blurry vision (12%), cognitive fog (9%), dysphoria (5%) and vomiting (4%). Notably, only 7% of encounters had discontinued therapy early because of the adverse events the patients experienced.

"Ketamine, a NMDA receptor antagonist, has emerged as potential therapeutic option for this population and has demonstrated benefit in other chronic pain syndromes and refractory mood disorders. Unfortunately, there is a paucity of literature available about the efficacy and tolerability of IV ketamine in the treatment of refractory pediatric headaches and status migrainosus." Rosenthal et al noted.

Rosenthal S, Ackley E, Koehler A, Yonker M. The Safety and Efficacy of Intravenous Ketamine in the Treatment of Refractory Pediatric Headache. Presented at: AHS Annual Meeting, 2023; June 15-18.

The Safety and Efficacy of Intravenous Ketamine in the Treatment of Refractory Pediatric Headache
Rosenthal S1, Ackley E, Koehler A, Yonker M
Children's Hospital Colorado, 13123 E. 16th Ave, United States

Intravenous ketamine represents a safe, tolerable, and efficacious treatment option for pediatric patients with refractory headaches.

Background: Patients with severe and refractory headaches often have few options for treatment despite ongoing pain and significant disability. While intravenous dihydroergotamine (IV DHE), an ergot derivative with 5HT agonism, is often effective for the majority of pediatric patients presenting with status migrainosus and refractory headaches, a significant proportion of patients will fail to respond or cannot receive IV DHE due to intolerability/contraindications. Ketamine, a NMDA receptor antagonist, has emerged as potential therapeutic option for this population and has demonstrated benefit in other chronic pain syndromes and refractory mood disorders. Unfortunately, there is a paucity of literature available about the efficacy and tolerability of IV ketamine in the treatment of refractory pediatric headaches and status migrainosus.

Methods: We conducted a retrospective chart review of patients 5-21 years old, admitted to a tertiary pediatric referral center between 2019-2022 for the treatment of refractory headache with continuous intravenous ketamine. Patients were excluded if they received both ketamine and IV DHE in the same encounter, had a secondary etiology for headache, or had a pain score < 3 (on verbal analogue scale, 0-10) at presentation. Primary outcome measures were percent pain reduction at discharge ([Discharge Pain Score - Initial Pain Score]/Initial Pain Score*100), serious adverse events, medication side effects, headache recurrence within 72 hours, and headache recurrence within 30 days post-discharge. Recurrence was defined as phone call or re-presentation to care for headache requiring rescue therapy. Demographic variables were also collected.

Results: 58 encounters comprised of 38 unique patients were included for analysis. The median age was 15.8 years (IQR 13.42-17.41) and 44/58 (76%) of patients identified as female. The most common diagnosis was chronic migraine without aura (45/58, 78%) and the median duration of headache or headache pain exacerbation at presentation was 10 days (IQR 3-26.5). The median maximum dose of ketamine was 0.28 mg/kg/hour (IQR 0.2-0.4) and the median duration of infusion was 3 days (IQR 2-3). The median percent pain reduction at discharge was 50% (IQR -67% to +25%). 37/58 (64%) of patients did not have headache recurrence or exacerbation with 1 month of discharge. Of those that recurred, the median time to recurrence was 7 days (IQR 3-12.5). 5/58 (9%) had recurrence with 72 hours of discharge. There were no serious adverse events. The most common side effects were dizziness (19%), nausea (12%), hallucinations (12%), blurry vision (12%), cognitive fog (9%), dysphoria (5%) and vomiting (4%). 4/58 (7%) encounters terminated therapy early due to side effects.

Conclusion: Intravenous ketamine is an effective, safe and well tolerated treatment option for refractory pediatric headaches and status migrainosus. There was a median pain reduction of 50% at discharge and nearly two-thirds of patients did not re-present for further rescue therapies within 1 month. There were no serious adverse events and side effects were very well tolerated.

Friday, July 7, 2023

IRF2BPL mutations

Inspired by a colleague's patient

Horovitz DDG, de Faria Domingues de Lima MA, Pires LC, Campos Araujo AQ, Vargas FR. Neurological Phenotypes of IRF2BPL Gene Variants: A Report of Four Novel Variants. J Cent Nerv Syst Dis. 2023 Jun 13;15:11795735231181467. doi: 10.1177/11795735231181467. PMID: 37346291; PMCID: PMC10280516.


IRF2BPL gene variants have recently been associated to developmental disability and epilepsy in children and movement disorders in adults. So far, only few cases have been reported; here we present four novel cases identified by exome sequencing, while investigating developmental delay, adult-onset cerebellar ataxia or regression.

Costa C, Oliver KL, Calvello C, Cameron JM, Imperatore V, Tonelli L, Colavito D, Franceschetti S, Canafoglia L, Berkovic SF, Prontera P. IRF2BPL: A new genotype for progressive myoclonus epilepsies. Epilepsia. 2023 Feb 21. doi: 10.1111/epi.17557. Epub ahead of print. PMID: 36810721.


The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.

Pisano S, Melis M, Figorilli M, Polizzi L, Rocchi L, Giglio S, Defazio G, Muroni A. Neurological phenomenology of the IRF2BPL mutation syndrome: Analysis of a new case and systematic review of the literature. Seizure. 2022 Jul;99:12-15. doi: 10.1016/j.seizure.2022.04.010. Epub 2022 Apr 18. PMID: 35525099.


Background: IRF2BPL is an intronless gene that was mapped to 14q24.3 chromosome in 2000 and codes for the interferon regulatory factor 2 binding like protein.

Objective: To analyses the clinical characteristics of the patients reported in the literature and of an additional patient we observed in order to better delineate the phenomenological spectrum of the disease and provide indications to improve clinical recognition and facilitate diagnosis.

Methods: We reported on 28 patients carrying the IRF2BPL mutation who were identified in 10 papers (n.27), using PUBMED as the search engine, and in our hospital (n. 1).

Results: All patients shared developmental delay/regression. Additional neurological symptoms were present in a large proportion of patients and reflected the involvement of five main neurological domains, i.e. epilepsy, dystonia, ataxia, spasticity, and ocular disturbances. Correlation analysis suggested a significant positive correlation between the number of affected neurological domains and the presence of MRI abnormalities (rho = 0.45, p = 0.02), while no significant correlation emerged between the number of affected clinical domains and age at disease onset (rho = 0.18, p = 0.35) or variant type (rho = 0.30, p = 0.12).

Conclusions: Our analysis highlights that the IRF2BPL mutation syndrome is highly specific to the central nervous system. Diagnostic work-up should consider the clinical picture of the IRF2BPL mutation syndrome herein delineated and the existence of conditions that share developmental delay/regression and result from acquired/genetic or unidentifiable underlying etiology.

Shelkowitz E, Singh JK, Larson A, Elias ER. IRF2BPL gene mutation: Expanding on neurologic phenotypes. Am J Med Genet A. 2019 Nov;179(11):2263-2271. doi: 10.1002/ajmg.a.61328. Epub 2019 Aug 20. PMID: 31432588.


Heterozygous loss of function variants in the IRF2BPL are a newly described cause of neurodevelopmental disabilities and epilepsy. As of 2019, fewer than 20 patients have been described in the published literature. This article reports an additional case of a patient with a pathogenic IRF2BPL variant and offers a comprehensive review of the published cases of individuals with IRF2BPL variants, in order to help expand the phenotype. The patient has a history of infantile spasms evolving into drug-resistant epilepsy with underlying epileptic encephalopathy consistent with Lennox-Gastaut syndrome. While at the extreme end of the spectrum, his phenotype is consistent with those previously described. Our literature review highlights the wide range of phenotypes exhibited by those with diseases related to IRF2BPL gene variants. This article also briefly discusses other comorbidities seen in the patient and those previously reported. While the molecular underpinnings of the role of IRF2BPL gene in the central nervous system are newly established, the specifics of its effects elsewhere have yet to be delineated. Furthermore, its pathogenesis in other organ systems is not yet understood and could be of importance from a management perspective.

Wednesday, July 5, 2023

Medical child abuse allegation

A new documentary highlights the story of a 10-year-old girl who was admitted to a Florida children's hospital for severe pain and then promptly removed from the custody of her parents after staff accused them of "medical abuse."

Netflix's "Take Care of Maya" follows the story of Maya Kowalski and her mother, Beata Kowalski, a registered nurse, as they navigate Maya's rare, chronic neurological condition called complex regional pain syndrome (CRPS) – a poorly understood affliction that causes severe pain throughout a person's body due to nervous system dysfunction, according to the Cleveland Clinic. 

"We, as parents, try to do the best we can for our children," Jack Kowalski, Maya's father and Beata's husband, says in the documentary. "You do everything for them. That's what Beata and I did. But there's nothing that could have prepared me for what I went through with my family. Nothing."

Dr. Anthony Kirkpatrick, who specializes in pain relief, initially diagnosed Maya with CRPS when she was 9 years old and helped her get treatment for the illness, which included doses of ketamine to help dull her pain. The treatment worked for a while, until she relapsed at age 10 in 2016.

She was admitted to Johns Hopkins All Children’s Hospital (JHAC) in St. Petersburg, Florida, after the relapse. Her symptoms included "episodes" of severe pain on her limbs and skin lesions. Her feet would also turn inward when she was experiencing CRPS episodes – a common reflex for patients experiencing pain from CRPS.

Her mother, who took meticulous notes regarding Maya's illness due to her experience as an R.N., insisted with doctors and nurses at the children's hospital that Maya had been diagnosed and CRPS, and doses of ketamine help with her pain. 

Hospital staff interpreted her insistence as hostility and did not believe everything she said about her daughter's condition.

As Beata demanded staff allow Maya to take ketamine to ease her pain, Dr. Sally Smith, medical director of the Pinellas County child protection team, intervened and accused Beata of medically abusing her daughter – an accusation the hospital still stands by after a Sarasota County court determined that staff had reasonable cause to suspect abuse.

Doctors called the Florida Department of Children and Families (DCF) to report their suspicions of medical abuse. Maya was put into the custody of child protective services worker Catherine Bedy at the hospital, where she remained for months without seeing her parents. 

"[W]hen Beata arrived and told them about Maya's medical history, including multiple visits to different specialists to diagnose her CRPS, and ultimately that ketamine infusions were the only thing that worked, instead of checking out her story, they became offended at her directness and certainty," attorney Greg Anderson explained. "None of them had any expertise in pain management, CRPS or ketamine treatments."

He added that Smith "determined that because Maya had been treated by a number of physicians before being properly diagnosed and because [Smith] disagreed with the ketamine infusions as a treatment," her mother Beata was exhibiting signs of "Munchausen by proxy."

Munchausen by proxy is a psychological disorder in which an abusive parent or caretaker makes up or causes an illness for an individual in their care who is not actually ill. People impacted by the disorder seek attention and sympathy, according to the Cleveland Clinic.

Smith allegedly ignored communications from Kirkpatrick, who attempted to explain Maya's CRPS and ketamine treatment to JHAC staff.

A legal battle ensued as Maya remained in DCF custody while she continued treatment at JHAC. In the documentary, Maya says she did not experience much improvement in her condition during her time at the hospital.

"Maya was kept in custody for three and a half months, isolated from her family, her friends, her attorney and even her [p]riest," Anderson said. "Johns Hopkins told the court that Beata was a danger to her daughter and shouldn’t even be allowed to talk to Maya unless supervised by a Johns Hopkins social worker and then only once a week. Eventually, she had no contact with her daughter."

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

"Therefore, we follow federal privacy laws that limit the amount of information we can release regarding any particular case. Our first responsibility is always to the child brought to us for care, and we are legally obligated to notify [DCF] when we detect signs of possible abuse or neglect," the hospital said. "It is DCF that investigates the situation and makes the ultimate decision about what course of action is in the best interest of the child."

A legal battle ensued, at which point DCF took custody of Maya as she continued treatment at Johns Hopkins without much improvement, as Maya explains in the documentary. (Netflix/"Take Care of Maya")

A motion to obtain immunity from the hospital states that Beata Kowalski once stated that Maya was in so much pain, she "wants to go to Heaven." Another time, Beata allegedly said she "may as well consult hospice so she can finally get enough medication and just let her die because she doesn't deserve to live this way," the motion states. 

Doctors who consulted with Beata and Maya prior to her time at JHAC also accused Beata of medical abuse, according to the motion. In 2015, Dr. Elvin Mendez wrote that Maya's illness was "all being driven by the mother." Also in 2015, doctors at Children's Lurie Hospital in Tampa flagged "abuse behavior" from Beata.

An investigation revealed that Beata filled out fraudulent prescriptions for her daughter's medication and administered them to Maya through a port at home, according to the motion.

The hospital also alleged that Maya's demeanor would change when her mother entered her hospital room. In an interview between police and Maya's father, Jack Kowalski, Jack agreed that part of Maya's condition appeared to be psychological, a transcript from the interview shows.

Doctors and detectives frequently returned to the fact that Maya would, at times, appear to be acting like a normal child without pain, and then the pain would come on suddenly when she was asked about it or when her parents were present. Maya said in the documentary, however, that her pain would come and go in waves, as is normal for people experiencing CRPS.

After Johns Hopkins delayed legal procedures in Maya's case, Beata hung herself in the garage on Jan. 7, 2016, "to free her daughter," Anderson said. "Maya was dying under Johns Hopkins mismanagement and terrible care."

Following Beata's suicide, two doctors assigned to Maya's care exchanged the following messages, obtained by Netflix, with each other:

Doctor No. 1: "Learned today ketamine girl’s mom committed suicide yesterday. Sorry to say my prediction was correct."

Doctor No. 2: "OMG…this is terrible. I know we did the right thing, but this is really f---ed up. I feel bad."

Doctor. No. 1: "I had another mother do this same thing. We definitely did the right thing for the child."

The Kowalskis are suing Johns Hopkins and Bedy, arguing that they "abducted, incarcerated and abused" Maya when she was 10.

The Sarasota County lawsuit mentions an incident that is also discussed in the film when Bedy stripped Maya of her clothing down to her underwear and then took photos of her without permission from her parents. Bedy said in court that the photos were taken for legal purposes, as seen in the doumentary.

Smith and her employer, Suncoast Advocacy Services, were initially named in the lawsuit but settled with the Kowalskis for $2.5 million. She has since retired, according to The Cut.

Anderson said parents need to protect themselves and keep copies of all their children's medical records as they are created.

"If your child has a complex illness, be very careful in ERs and anywhere you don’t have a relationship with the doctors," he said. "Do not trust the system. You don’t need to be paranoid, but the first time you get a feeling the doctor may not have your child’s interest at heart, or that they are acting strangely in their questioning and examination, ask direct questions of why they are there and who they work for."

"Sally Smith was famous for impersonating a treating physician, with a Johns Hopkins lab coat and an act that was designed to lure unsuspecting parents into divulging what the parents thought were innocent facts and history about their child, but Smith had… verbal traps," he continued.

The end of the documentary features interviews with multiple other parents accused of medically abusing their children – some of whom were jailed for the alleged crime while most others agreed to a "case plan," which is essentially an agreement parents make with hospitals to get their children back in their custody.

"Parents who have children with… complicated medical conditions, and some who have had their own experiences in the child welfare system are reaching out and saying that 'Take Care of Maya' is giving them the will to keep fighting for their children and families," producer Caitlin Keating told Fox News Digital. "They have now found the courage to speak out and tell their personal stories on social media. We hoped that this film would spark a larger conversation and we see it doing just that."

One woman told Keating that "Take Care of Maya" shows families "aren't alone," and it gives them "hope that life can go on and it can get better."

"Thank you for being the voice for so many families that have been forced silent," the woman wrote.

Trial proceedings in the Kowalskis' case against Johns Hopkins and Bedy have been pushed to Sept. 11.

Tuesday, July 4, 2023

Spina bifida and severe intrauterine hydrocephalus

The Ashley treatment

Ashley is young woman who was born in 1997 with a severe mental and physical disability that prevented her from ever eating, walking or talking by herself. Her mental capacity was also not expected to develop further than that of an infant. In 2004, When she was six and a half years old, Ashley‘s parents and the Seattle Children’s hospital physicians who had been treating her sought to perform on Ashley a novel medical intervention that would include hormonal treatment for growth attenuation, surgical removal of her breast buds, and a hysterectomy. This surgical intervention was presented as beneficial to Ashley by allowing her parents to take care of her longer and postpone institutionalization. The removal of breast buds and hysterectomy were meant to spare Ashley the pain and discomfort of menstruation and the development of fully-developed breasts, and also to “avoid sexualization” in order to make her less vulnerable to sexual abuse when she was ultimately institutionalized.

Here is a slide, apparently made by Ashley’s father, which explains the theory behind the treatment:

Among the dozens of issues this controversial treatment raised was the lack of a court order authorizing the treatment. According to the investigative report conducted by the Washington Protection & Advocacy System (WPAS), the planned intervention was brought before an ethics committee, which approved it but nevertheless advised the family to seek court approval for the hysterectomy. According to the report, Ashley’s parents didn’t seek court approval but rather consulted with their attorney who advised them that, according to Washington state law, court approval is not needed for the sterilization of minor patients with developmental disabilities when sterilization is not the “sole purpose” of the procedure. This position was accepted by the children’s hospital, which went ahead with the treatment, but later expressed regret.

The question in which I’m interested is why a court review is required only for the sterilization component of the “Ashley treatment,” as it has come to be known, but not for the general growth attenuation and the de-sexualization aspects. Here are some of my preliminary thoughts:

The legal protection against involuntary sterilization was developed through the constitutional protection on liberty and privacy in the Fourteenth Amendment. As for the specific context of medical decision-making for minors, the departure point is the strong protection over family privacy allowing parents almost full capacity to make decisions on behalf of their minor children. Washington state law generally limits parental authority by a court review for highly invasive and irreversible treatments. Sterilization has been recognized to require a separate representation of the minor patient by a third party in an adversary hearing (guardian ad litem).

Legal protection against forced sterilization is bound with American engagement with eugenics laws, which prevailed in the first half of the 20th century and were disaffirmed gradually by the states in the second half of the century. However, developments in endocrinology and surgery over the past several of decades have generated an array of medical interventions for children that are highly similar in their invasiveness and irreversibility to sterilization. In fact, combinations of hormonal and surgical interventions are already used to control and manipulate different aspects of children’s sexuality, not just in cases of intersex infants and Trans youths, but also in Ashley’s case – by keeping her child-like. It appears that, currently, only procreation is a protected liberty interest, yet sex selection, change, and attenuation, are fair game for parents and physicians.

I am not arguing that these types of intervention necessarily impose upon a minor patient’s liberty interests, but rather wonder: was Ashley’s liberty interest preserved under this model? It may very well be that due to her severe disability even a court review looking more closely at the issue would have come to the same result and approved the hysterectomy.  However, what about her de-sexualization? I do not think that the removal of breast buds or a uterus (or any other human organ for that matter) is in fact de-sexualizing. I do believe, though, that the endeavor to infantilize her physically may have prevented the opportunity to explore her growing body and sensory tissues that come with it. It may be that one of Ashley’s liberty interests was vested in the potential pleasure from her developing body. Ashley’s case is extremely rare and unique, yet it invites us to revisit our attitudes towards children’s sexuality in light of new scientific innovations, and ask whether their liberty interests in their bodies spread beyond procreation.,when%20she%20was%20ultimately%20institutionalized.

Monday, July 3, 2023

Zolgensma story

By all accounts, 3-year-old Granger Smith is a typical preschooler. He loves dinosaurs and being outside, and he's his older siblings’ biggest fan.

“He loves his evenings at the ball fields,” said his mom, Heather Smith.

This past year, Granger successfully finished up his first year of preschool, where he quickly made friends and adored his teachers and aides. These are big achievements for any toddler, but especially for Granger.

“We still get emotional when we see him doing things that we were told might never happen,” said Smith.

The Smith family’s world was turned upside down in the fall of 2019. Just days after the flood of emotions of welcoming their third child into the world, they received a phone call from their pediatrician urging them to head to the emergency department at the Univeristy of Kentucky Albert B. Chandler Hospital.

The family made the two-hour drive from their home in Greenup County to Lexington. During the drive, they tried to process the news: their seemingly perfect baby boy had abnormal results on his newborn screening for spinal muscular atrophy (SMA). SMA causes weakness of muscles due to cells dying in the spinal cord. The cells die because they do not make a necessary protein. This disease is the number one genetic cause of infant death, despite it being considered rare.

SMA is a progressive disease, and unfortunately there are not many treatment options. David Neil Toupin, M.D., a child neurologist at Kentucky Children’s Hospital, says the newborn screening for SMA, which Granger received due to a change in state regulations just shortly before his birth, plus the urgency of his family to get to UK are critical pieces to his story.

“Early detection is extremely important. It is the most important thing, really," Toupin said. "The treatments can preserve the health of the cells of the spinal cord, but if those cells are already dead, they cannot be brought back.”

“When you receive a life-changing diagnosis for your child, you can only hope that the outcome could be as great as it has been for Granger,” said Smith.

In December of 2019, at only six weeks old, Granger became the first child to receive a brand-new treatment known as Zolgensma at UK HealthCare. The gene therapy had just been approved by the U.S. Food and Drug Administration (FDA) months earlier.

“He still had a lot of those cells alive to be saved,” said Dr. Toupin. There were certainly still hurdles as far as insurance coverage and logistics of getting the treatment to Granger since it was so new at the time, but still the family and team at UK HealthCare were all determined to move as quickly as possible.

“It is not a situation that I would want anyone to go through, but it is something that we had to push through for our child," said Smith. "We had to be strong for him. He needed to see his parents would do anything for him.”

Since Granger received his infusion, seven other newborns have received Zolgensma at UK HealthCare. Toupin has walked through the process with each of these families.

“It is a heart-wrenching experience," he said. "Even if you know what SMA is ahead of time, it is still a whirlwind. And for those who do not know what SMA is, it is a complete shock followed by a rapid series of events to try to save their child. It is not easy.”

The collaboration that exists at an academic medical center like UK is invaluable as Toupin and others help families navigate the diagnosis and treatment options.

“It requires frequent education and a team approach," said Toupin. "There are so many people involved. From genetics, neurology, infusion nurses, therapists, laboratory services, and pharmacy. We are one big team for these kids.”

As Toupin and the rest of the team at UK work each day to help kids and families like Granger’s, they pull inspiration from their first patient to take this journey.

“Everybody was in shock the first time they saw Granger in clinic. Every time we see him back, we continue to be amazed,” said Toupin. “He is writing his own story and we are all just following along at this point. It is an outstanding experience for us as providers to be able to see, given what this disease used to be like before the treatment. Previously, most of these babies died. They didn’t achieve motor milestones anywhere close to what Granger is doing.”

The active toddler has a full schedule of appointments each week with various therapists. The work is all standard for someone like Granger and is important as he develops for his providers to watch for any signs of weakness.

“We want to make sure kids continue to gain skills. Fortunately, with the treatment, as we see with Granger, kids are doing well. But we still have to be cautious because this is still relatively new,” said Toupin. “We don’t know exactly what long-term looks for them. We want to make sure kids don’t start losing skills, because there are other treatments we can potentially offer them.”

The frequent monitoring of progress or setbacks is another reason Toupin says being at a multidisciplinary center is huge. “When I see Granger in clinic, I see him with physical, occupational, and speech therapists simultaneously. That allows us to get a comprehensive view of him and where he is,” said Toupin.

Thinking back to when they first received the SMA diagnosis, Heather Smith says in that moment, they had no idea where their lives were going or what it all would look like today. While each day is busy juggling all the various appointments and activities for their family, she says they are thankful for each chapter they have lived through.

“We now always remember to stop and appreciate the little things in life,” said Smith.

Just as his story that is still being written provides motivation for his providers, other families going through a similar situation also pull inspiration from Granger – and his parents.

“They have been so supportive of our other families, and it is helpful for them to know there is a community of people who have gone through the same thing,” said Toupin.

Smith says their message to other families is to get treatment as soon as possible and to be their child’s biggest advocate.

“These treatments can’t reverse the damage already done, but they can certainly stop it from progressing,” said Smith. The proof is in each step she watches her son take and each milestone he meets.

“We still don’t know what the future holds for him and there are a lot of what ifs, but we do know we enjoy every day and every new first we have with him,” said Smith. "We would not be where we are today without Dr. Robertson and Dr. Toupin and all the people at UK that have helped us along the way. Granger has been very blessed with the neurology team he has on his side."