Wednesday, May 27, 2020

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

Something about which I have often wondered

Sathe AG, Elm JJ, Cloyd JC, et al. The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus [published online ahead of print, 2020 May 18]. Epilepsia. 2020;10.1111/epi.16534. doi:10.1111/epi.16534

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group

Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. Lancet. 2020;395(10231):1217‐1224. doi:10.1016/S0140-6736(20)30611-5


Background: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.

Methods: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in, NCT01960075.

Findings: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.

Interpretation: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.

Sunday, May 24, 2020

The incubator doctor

Nurses in starched white uniforms and doctors in medical coats tended to babies in glass and steel incubators. The infants had been born many weeks premature and well below a healthy birth weight. Stores didn’t make clothes small enough to fit their tiny, skeletal frames so the nurses dressed them in dolls’ clothes and knitted bonnets.

A sign above the entrance read “Living Babies in Incubators” in letters so large they could be read from the other end of the Chicago World’s Fair grounds, which took place over 18 months in 1933 and 1934. The infant incubator exhibit was built at a cost of $75,000 (worth $1.4 million today) and was painted in a patriotic red, white and blue.

The men in charge were leading Chicago pediatrician Dr. Julius Hess and Martin Couney, who was known across America as “the incubator doctor.” Couney was a lugubrious man in his 60s, with thinning gray hair, a mustache and a stoop, something he jokingly attributed to a lifetime of bending over babies. Couney and Hess employed a team of six nurses and two wet nurses.

Martin Couney had run infant incubator exhibits, in which premature babies were displayed to the public, for more than three decades, most famously at Coney Island in New York City. He had long been regarded by desperate parents as a savior, one who offered medical help to babies written off as “weaklings” by mainstream medicine.

But for Hess, who was accustomed to carrying out his work in a more conventional hospital setting, this was a career first.

The exhibit was a hit with the Chicago public who paid 25 cents and flocked by the hundreds of thousands to see the babies…

To celebrate the success of their facility, Couney organized a “Homecoming” celebration on July 25, 1934, for babies who had “graduated” from the incubators at the Chicago’s World’s Fair the previous summer. Of the 58 babies Couney and Hess had cared for in 1933, 41 returned with their mothers for the reunion. The event was broadcast live on local radio and across the fairgrounds.

On the radio program, Couney’s exhibit was portrayed by the announcer not as a frivolous sideshow spectacle, but as an invaluable medical facility:

The Incubator station for premature babies…is not primarily a place of exhibiting tiny infants. Instead, it is actually a lifesaving station, where prematurely born babies are brought from leading hospitals all over the city, for the care and attention that are afforded. The place is spick and span, with doctors and graduate nurses in constant attendance...

Because of the sideshow setting in which he operated, Couney’s career had always been controversial. Many in the medical professional viewed the “incubator doctor” with suspicion, others with outright hostility. The New York Society for the Prevention of Cruelty to Children had repeatedly accused Couney of exploiting the babies and endangering their lives by putting them on show. .   

None of the complaints was sustained, and by the 1930s, Couney was finally being taken seriously as a medical pioneer. Couney’s professional collaboration with Hess marked a key stage in his habilitation.

But while doing research for my radio documentary Life Under Glass, which is being broadcast on NPR stations around the country this August, and my book, Miracle at Coney Island, I made an incredible discovery about a man who has a claim to have changed the course of American neonatal medicine.

Couney never actually qualified as a medical doctor.

Throughout his career, Couney said he had studied medicine in Leipzig and Berlin. However, I could find no evidence of Couney (or Cohn/Cohen as he was known then) having studied medicine at a university in either city. To become a physician in Germany, one was required to write a thesis. The U.S. National Library of Medicine has copies of the German records: the librarians could not locate a thesis written by Couney.

Couney was deliberately evasive about his date and place of birth. I have discovered that he immigrated to the US in 1888 at 19 years old. But someone of that age would not be old enough to have studied at university in Leipzig and Berlin before going on to do graduate work in Paris at the knee of Pierre Budin, the father of European neonatal medicine, as Couney claimed to have done in numerous press interviews.

In the 1910 U.S. census, Couney listed his career as, “surgical instruments.” Though Couney claimed to be the inventor of an incubator, I have been unable to find any evidence that he registered an incubator patent in the U.S. More likely Couney was a technician. Yet by 1930 he was describing himself in the census as a “physician.”

Over time, the success of Couney’s facility began to attract the attention of some of America’s leading pediatricians. Right up until the late 1930s, few American hospitals had incubators, so doctors sent premature babies to him.

Couney took in babies from all backgrounds, regardless of race or social class, a remarkably progressive policy, especially when he started out. He did not take a penny from the parents of the babies. In 1903 it cost around $15 (equivalent to around $405 today) a day to care for each baby; Couney covered all the costs through the entrance fees.

Presumably unaware that Couney was not a qualified doctor, pediatricians began coming to the fairgrounds to collaborate with Couney and study the babies in his care.

The distinguished Yale professor, pediatrician and child developmental psychologist Arnold Gesell visited Couney multiple times at the 1939 New York World’s Fair. Gesell brought a cameraman with him to film the babies in Couney’s facility.

Interestingly, when Gesell wrote his book, The Embryology of Behaviour: The Beginnings of the Human Mind, he avoided any mention of Couney or the sideshow setting where he had carried out much of his research. By contrast, when in 1922, Hess wrote the first textbook on premature birth published in the U.S., Premature and Congenitally Diseased Infants, he wrote, “I desire to acknowledge my indebtedness to Dr Martin Couney.”

Of all Couney’s professional associations, his friendship with Morris Fishbein, the controversial president of the American Medical Association (AMA), is the most intriguing.

Fishbein was head of the AMA for 25 years and led the Association’s crusade against “quack” doctors. The two men were so close, Fishbein sent his aspiring medic son, Justin, to discuss his career with Couney in New York.

If he had been found out, Couney could have faced a large fine and a lengthy prison sentence.

Over the course of his nearly 50-year career, Couney took in around 8,000 babies, of whom he claimed to have saved around 6,500. While there is no way of verifying the numbers, pediatricians today acknowledge that the team of doctors and nurses which Couney assembled was highly skilled, ensuring the babies got the best care available in America at that time.

For this reason, Dr. Lawrence Gartner, pediatrician and professor emeritus at the University of Chicago believes Couney was an important figure in American medical history.

“I wouldn’t dismiss Martin Couney at all,” says Gartner. “Martin Couney was well-respected by the medical community at that time. His operation was highly respected and well-known to physicians.”

To his former graduates, Couney is a hero to whom they owe their lives. They talk of him as the only man who believed they were worth saving, and, crucially, who was prepared to care for them without charge.

Kathy Meyer was born eight weeks premature in 1939. She was taken to Cornell University’s New York Hospital, which had just opened a training and research center for premature infants, the first facility of its kind on the Eastern Seaboard. When Meyer’s parents were told she’d need to stay in the hospital for several months and realized they couldn’t afford to pay the bills, her pediatrician suggested they send her to Martin Couney at the New York World’s Fair.

Couney sent his incubator ambulance straight to the hospital to collect her.

“I was a sickly baby,” said Meyer. “If it wasn’t for Couney, I wouldn’t be here today. And neither would my four children and five grandchildren. We have so much to thank him for.”

Courtesy of a colleague

Therapy for progressive myoclonic epilepsy

Josef Finsterer, Fulvio A. Scorza, Ana C Fiorini and Carla A. Scorza. Mitochondrial myoclonic epilepsy requires specific treatment . Seizure, in press.

With interest we read the review article by Orsini et al. about myoclonic epilepsy in Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers (MERRF), and sialidoses type 1 and 2. The authors recommend valproic acid (VPA) as first choice for myoclonic epilepsy irrespective of the underlying cause followed by lamotrigine (LTG), primidone (PRM), phenobarbital (PB), and levetiracetam (LEV). Other anti-seizure drugs (ASD) that can be considered for myoclonic epilepsy include topiramate (TPM), zonisamide (ZNS), ethosuximide (ESX), felbamate (FLB), benzodiazepines (BZD), and perampanel (PER). We have the following comments and concerns.

We do not agree that VPA can be recommended as the first line ASD most frequently applied in myoclonic epilepsy for all types of diseases associated with myoclonic epilepsy, including MERRF. MERRF is an ultra-rare mitochondrial disorder (MID) clinically diagnosed if the four canonical features myoclonus, generalised epilepsy, ataxia, and myopathy are present. If additional phenotypic features occur, the term MERRF-plus is applied. From VPA it is well known that it can be mitochondrion-toxic  and that it should be avoided in these conditions, since it can be even fatal. Particularly in MIDs due to POLG1 mutations fatal acute liver failure has been reported after application of VPA. Also from PB it is known that it can be mitochondrion-toxic. Thus, therapy of myoclonic epilepsy in MERRF or other MIDs should be at variance from conditions other than MERRF discussed in the review. In recent publications it has been shown that LEV and clonazepam (CLZ) are the ASDs of choice for myoclonic epilepsy in MIDs, particularly MERRF syndrome.

The authors mention that MERRF may be due to mutations in MT-TK, MT-TL1, MT-TH, MT-TS1, MT-TS2, or MT-TF. However, the variant m.8342 G > A in MT-TK has been classified as only possibly pathogenic. Also the variant m.12207 G > A in MT-TS2 has been classified as only possibly pathogenic. [The authors do not mention that MERRF may be also due to mutations in MT-ND3 or MT-TW , and probably due to variants in MT-ND5. There are also indications that MERRF can be caused by mutations in POLG1. Altogether 26 pathogenic variants causing a MERRF phenotype have been identified so far.

The authors mention that the MIDs most frequently associated with epilepsy are MERRF and Alpers Huttenlocher disease (AHD). However, it should be included that also mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA) syndrome, and Leigh syndrome frequently manifest with seizures. Occasionally, epilepsy is a phenotypic feature in infantile onset spinocerebellar ataxia (IOSCA) syndrome, Kearns-Sayre syndrome (KSS), Leber’s hereditary optic neuropathy (LHON), leucoencephalopathy with brainstem and spinal cord and lactate elevation (LBSL), or neuropathy ataxia, and retinitis pigmentosa (NARP) syndrome.

In summary, myoclonic epilepsy in MIDs, including MERRF, should be treated differentially to myoclonic epilepsy in other hereditary syndromes. The most appropriate ASDs for myoclonic epilepsy in MIDs are LEV and CLZ. Mitochondrion-toxic ASDs should be strictly avoided as first line ASDs. The genetic background of MERRF is more variegated than anticipated.

Orsini A, Valetto A, Bertini V, et al. The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy. Seizure. 2019;71:247‐257. doi:10.1016/j.seizure.2019.08.012

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.

Discussing sudden unexpected death in epilepsy with children and young people with epilepsy and their parents/carers

Cooper K, Kirkpatrick P, Brand C, Rolfe A, Florida-James S. Discussing sudden unexpected death in epilepsy with children and young people with epilepsy and their parents/carers: A mixed methods systematic review [published online ahead of print, 2019 Oct 13]. Seizure. 2019;S1059-1311(19)30137-2. doi:10.1016/j.seizure.2019.10.002


Purpose: To synthesise the quantitative and qualitative evidence on the views and experiences of children and young people with epilepsy (CYPwE), their family members/caregivers and healthcare professionals on conversations between healthcare professionals and CYPwE/caregivers about the possibility of sudden unexplained death in epilepsy (SUDEP).

Methods: Mixed methods systematic review in accordance with Joanna Briggs Institute methodology, PRISMA guidelines and guided by an a-priori protocol.

Results: 656 potentially relevant studies were identified, 11 of which fulfilled the inclusion criteria for the review: 6 quantitative studies, 4 qualitative studies and 1 opinion/text article. Data synthesis resulted in the following 2 integrated findings: (i) Caregivers, and where appropriate CYPwE, should be provided with information on SUDEP and how it relates to them; (ii) Information on SUDEP should be delivered face-to-face, with supporting written information, by a suitably knowledgeable healthcare professional whom the caregiver/CYPwE feels comfortable with, at an appropriate time at or close to diagnosis.

Conclusion: This review confirms that healthcare professionals should discus SUDEP with CYPwE and/or their caregivers at or around the time of diagnosis and that the discussion should include prevalence of SUDEP, risk factors and risk reduction methods relative to the individual concerned. Apart from delivering SUDEP information face-to-face, with written or online information provided to reinforce messages, there is a lack of evidence on "how" to impart this sensitive information. Further research exploring the most acceptable and effective methods of discussing SUDEP with CYPwE and their caregivers is therefore indicated.

Gelastic seizures involving the left parietal lobe

Machado RA, Astencio AG. Gelastic seizures involving the left parietal lobe. Epilepsy Behav. 2012;23(1):87‐89. doi:10.1016/j.yebeh.2011.11.009

Gelastic seizures have been described in various epilepsies arising from the temporal or frontal lobes, although the most commonly encountered form is related to the presence of a hypothalamic hamartoma. We describe a patient with gelastic seizures involving the left parietal lobe. Our patient, an 8-year-old girl, underwent interictal video/EEG monitoring and MRI. The seizures consisted of brief staring followed by smiling and laughing. Electroencephalography during the gelastic seizures showed rhythmic spikes and waves in the left parietal lobe. MRI revealed the characteristic features of focal cortical dysplasia. Our findings suggest that the left parietal lobe may actively participate in the particular epileptogenic network generating gelastic seizures.

Why do people Google epilepsy?

Brigo F, Igwe SC, Ausserer H, et al. Why do people Google epilepsy? An infodemiological study of online behavior for epilepsy-related search terms. Epilepsy Behav. 2014;31:67‐70. doi:10.1016/j.yebeh.2013.11.020

Millions of people worldwide use the Internet daily as a source of health information. Google is the most popular search engine and is used by patients and physicians to search for online health-related information. This study aimed to evaluate changes in web search behavior occurring in English-speaking countries over time for terms related to epilepsy and epileptic seizures. Using Google Trends, data on global search queries for the terms "epilepsy", "seizure", and "seizures" between January 2004 and September 2013 were analyzed. The reduction over time in search queries for the term "epilepsy" (and, to a lesser extent, "seizures") was counterbalanced by an increased trend in searches for the term "seizure". Most terms associated with the search queries were related to symptoms of seizures, especially tonic-clonic seizures, and to seizures occurring in children. Three peaks in search volume over the period studied corresponded to news of celebrities having seizures. The volume of searches for the term "epilepsy SUDEP" was found to be enormously increased over time. Most people appear to use search engines to look for terms related to epilepsy to obtain information on seizure symptoms, possibly to aid initial self-diagnosis. Fears and worries about epileptic seizures and news on celebrities with epilepsy seem to be major factors that influence online search behavior.

Saturday, May 23, 2020

Overdiagnosis 2

A Detroit-area doctor accused of misdiagnosing epilepsy in more than 200 children surrendered his medical license and agreed to pay a $5,000 penalty under a settlement accepted Wednesday by state regulators.

"A great day for patients that was long overdue," said attorney Brian McKeen, who has won two trials so far over Dr. Yasser Awaad’s treatment of children.

A disciplinary panel at the Michigan Board of Medicine accepted the agreement during a meeting held by video conference. There was no immediate response from Awaad’s attorney to a request for comment.

The attorney general's office filed a complaint against Awaad in 2018, years after he treated children as a pediatric neurologist at Oakwood Healthcare in Dearborn, which is now part of Beaumont Health.

"Between 1997 and 2007, (Awaad) misdiagnosed approximately 250 patients as suffering from epilepsy or seizure disorders, based on electroencephalograms that were either not performed or not interpreted properly," the complaint said. "Some of these patients were also misdiagnosed as having attention deficit disorder or other autistic spectrum conditions."

Children were given medication that was unnecessary and sometimes harmful, the complaint said, and their actual conditions weren't addressed. 

Awaad agreed with regulators that the allegations could be treated as true to resolve the complaint. He said he has not actively practiced medicine in Michigan since 2007.

McKeen represents dozens of patients who have accused Awaad of malpractice. During one trial last year, he said the doctor was running a "gravy train of fraud" by repeatedly ordering expensive EEG tests.

Awaad’s attorney told jurors that it was "outrageous and preposterous" to claim Awaad intentionally harmed Mariah Martinez when she was 9 years old. Harry Sherbrook said there was more to diagnosing epilepsy than reading EEGs.

The jury awarded more than $3 million to Martinez, although a judge reduced it to $846,000 because of state caps on malpractice claims. 

In a second case in October, a jury awarded nearly $2.8 million to a former Awaad patient. That verdict will likely be reduced, too.

Awaad's agreement to give up his medical license was not his first encounter with regulators. A similar complaint over his epilepsy diagnoses was filed in 2011. He paid a $10,000 fine and agreed to have his work reviewed by another doctor for a period.

Tuesday, May 19, 2020

Triumph over adversity 6

Chase Smith’s looming death did not stop him from marrying the love of his life.

The terminally ill Indiana high school senior melted hearts nationwide after he wed his girlfriend upon learning that he had only months to live.

Smith, 18, had reportedly been talking about tying the knot with Sadie Mills for some time, but decided to make it official due to his tragic prognosis, reports the Indy Star.

“He is all that matters to me,” says Mills, 18, who wed Smith on the same spot on her parents’ driveway where they exchanged their first kiss six months ago. The Indian Creek High School student reportedly broke down in tears upon seeing his future wife, who goes to Mooresville High School, in her wedding gown.

It had been a whirlwind romance for the two seniors, who hit it off during a swim meet between their rival schools late last year.

“I thought she was pretty cute,” says Smith, who reportedly called Mills over to talk and then asked for her phone number.

At first, the nationally ranked swimmer didn’t know if he’d have the time for their first date due to his busy schedule of swim meets and SATs. However, Smith changed his tune after Mills told him, “If you’re really interested, you’ll find time.”

Since then, the two high school sweethearts have been inseparable, going everywhere from church to the movies together, reports the Indy Star.

“We just fell in love with each other’s personality,” says Mills, who calls her beau a “good Christian boy.”

It wasn’t just a case of puppy love. The blossoming lovebirds planned to marry after college — something they discussed during deep, hours-long conversations on the couch.

Then, tragedy struck. The bone cancer that Smith had been battling since he was 12 returned with a fury in April, with tumors flaring up everywhere from his lung and hip to his skull and the lining of his brain, causing severe headaches. The prognosis was three to five months, with or without treatment. 

“Ewing’s [sarcoma] is extremely aggressive, extremely brutal,” his mom, Kelli Smith, tells the Indy Star of the rare cancer strain, which afflicts mainly children and young adults, according to WebMD. “He has fought a big fight, but he is tired.”

Knowing his time was fleeting, Smith decided to marry his sweetheart right away.

After receiving their parents’ blessings, the lovebirds planned the event in three days, and sealed the deal on April 29 with a kiss, as seen in this moving wedding montage posted on May 8.

Despite the tragic circumstances surrounding the ceremony, Smith described the moment as “pure joy,” a sentiment shared by his new bride.

He said that Mills had allowed him to “open up about my personal life and cancer journey” in a way that no one else could. “She is able to calm me down in a lot of scenarios when nobody else can,” he adds.

The bride’s father, Jeff Mills, posted footage of the wedding to Facebook on May 10 with the caption: “So happy to have this young man and his wonderful family in our lives. Thanks for making my baby girl so happy!”

“You just don’t see love like this,” gushed Smith’s proud mother.

Their marriage made waves outside the family circle as well.

“I’m crying happy tears for you two!” commented one fan under a wedding announcement on the Mooresville diving club’s Facebook page.

“Most people go through life and are never fortunate enough to find love like this,” added another on a repost by Jeff Mills of the wedding video.

A GoFundMe page set up to help pay for Smith’s cancer treatment has garnered almost $100,000 in contributions as of Tuesday afternoon.

“The precious people in your life, the amount of time they are in your life — take every moment you have,” says Smith. “Enjoy and give everything you can in those relationships.”

A review of online resources to explore mitochondrial genomics

Cappa R, de Campos C, Maxwell AP and McKnight AJ (2020) “Mitochondrial Toolbox” – A Review of Online Resources to Explore Mitochondrial Genomics. Front. Genet. 11:439. doi: 10.3389/fgene.2020.00439

Mitochondria play a significant role in many biological systems. There is emerging evidence that differences in the mitochondrial genome may contribute to multiple common diseases, leading to an increasing number of studies exploring mitochondrial genomics. There is often a large amount of complex data generated (for example via next generation sequencing), which requires optimised bioinformatics tools to efficiently and effectively generate robust outcomes from these large datasets. Twenty-four online resources dedicated to mitochondrial genomics were reviewed. This ‘mitochondrial toolbox’ summary resource will enable researchers to rapidly identify the resource(s) most suitable for their needs. These resources fulfil a variety of functions, with some being highly specialised. No single tool will provide all users with the resources they require; therefore, the most suitable tool will vary between users depending on the nature of the work they aim to carry out. Genetics resources are well established for phylogeny and DNA sequence changes, but further epigenetic and gene expression resources need to be developed for mitochondrial genomics.

Monday, May 18, 2020

Cerebellar cognitive affective syndrome in children with acute postinfectious cerebellar ataxia

Evald L, Evald J, Hansen D, Bonne NL, Hansen JK. Cerebellar Cognitive Affective Syndrome in Children With Acute Postinfectious Cerebellar Ataxia. Pediatr Neurol. 2020 Apr 8. pii: S0887-8994(20)30113-2. doi:10.1016/j.pediatrneurol.2020.03.019. [Epub ahead of print]

Acute postinfectious cerebellar ataxia is the most common cause of acute ataxia in childhood. One previous case study has suggested that cerebellar cognitive affective syndrome may be comorbid with acute postinfectious cerebellar ataxia, but this was not confirmed by formal assessments.

Children aged three to 15 years with a confirmed diagnosis of acute postinfectious cerebellar ataxia were invited to participate. Three patients were included and assessed by a pediatrician, neuropsychologist, and logopedist at the subacute stage (less than 14 days post-onset) and after six months and one year of follow-up.

All three children complied with the diagnostic criteria of cerebellar cognitive affective syndrome. The cognitive and affective symptoms persisted longer than the motor symptoms. Child A (girl, aged three years and eight months) was most severely affected with slow progression of motor cerebellar symptom; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up. Child B (boy, aged four years and four months) had more subtle motor cerebellar symptoms that swiftly remitted within the first week; the cerebellar cognitive affective symptoms were also more subtle. Child C (boy, aged seven years and eleven months) was considerably affected by motor cerebellar symptoms but showed marked improvement within the first month; the cerebellar cognitive affective symptoms had not entirely remitted at one-year follow-up.

Cognitive affective cerebellar syndrome may be an overlooked complication of acute postinfectious cerebellar ataxia. The severity of cerebellar cognitive affective symptoms seemed to correspond to the severity of the cerebellar motor symptoms, but the improvement was remarkably slower.

Sunday, May 17, 2020

Jahi McMath

In a petition to the Alameda County Superior Court, Dolan requested that a physician unaffiliated with the hospital examine Jahi. He wrote that the hospital had a conflict of interest, because if its doctors were found guilty of malpractice they could “drastically reduce their liability by terminating Jahi’s life.” In cases of wrongful death, California places a cap of two hundred and fifty thousand dollars on damages for pain and suffering. But there is no limit on the amount that can be recovered when a patient is still alive. In a separate motion, Dolan argued that the hospital was infringing on Nailah’s right to express her religion. He said that, as a Christian, she believed that her daughter’s soul inhabited her body as long as her heart beat…

Sandra said she sometimes wonders, “If the hospital had been more compassionate, would we have fought so much?”

Nailah asked Children’s Hospital to perform a tracheotomy, a surgery that enables ventilator air to be pumped directly into the windpipe—a safer way for Jahi to breathe when transported to a new hospital. The hospital’s medical-ethics committee unanimously concluded that the intervention was inappropriate. “No conceivable goal of medicine—preserving life, curing disease, restoring function, alleviating suffering—can be achieved by continuing to ventilate and artificially support a deceased patient,” they wrote. They said that the doctors and nurses caring for Jahi were experiencing “tremendous moral distress,” and that accommodating the family’s requests would raise “significant concerns of justice and fairness.”…

It wasn’t until they landed that she learned they were in New Jersey, one of only two states—New York is the other—where families can reject the concept of brain death if it violates their religious beliefs. The laws in both states were written to accommodate Orthodox Jews, some of whom believe, citing the Talmud, that the presence of breath signifies life…

Bioethicists also disparaged the family’s decision. In an op-ed in Newsday, Arthur Caplan, the founding director of N.Y.U.’s Division of Medical Ethics and perhaps the best-known bioethicist in the country, wrote, “Keeping her on a ventilator amounts to desecration of a body.” He told CNN, “There isn’t any likelihood that she’s gonna survive very long.” In an interview with USA Today, he said, “You can’t really feed a corpse” and “She is going to start to decompose.” Laurence McCullough, a professor of medical ethics at Cornell, criticized any hospital that would admit Jahi. “What could they be thinking?” he said to USA Today. “There is a word for this: crazy.”..

Legal ambiguities remained—people considered alive in one region of the country could be declared dead in another—and, in 1981, the President’s Commission for the Study of Ethical Problems proposed a uniform definition and theory of death. Its report, which was endorsed by the American Medical Association, stated that death is the moment when the body stops operating as an “integrated whole.” Even if life continues in individual organs and cells, the person is no longer alive, because the functioning organs are merely a collection of artificially maintained subsystems that will inevitably disintegrate. “The heart usually stops beating within two to ten days,” the report said…
Weisbard had previously served as the assistant legal director for the President’s Commission on death and, like Wikler, he felt uneasy about the result. He said, “I think that the people who have done the deep and conceptual thinking about brain death are people with high I.Q.s, who tremendously value their cognitive abilities—people who believe that the ability to think, to plan, and to act in the world are what make for meaningful lives. But there is a different tradition that looks much more to the body.” The notion of brain death has been rejected by some Native Americans, Muslims, and evangelical Protestants, in addition to Orthodox Jews…

Weisbard, a religious Jew, said that he didn’t think “minority communities should be forced into a definition of death that violates their belief structures and practices and their primary senses.”…
At St. Peter’s Hospital, a music therapist visited the intensive-care unit every few days. She stood next to Jahi’s bed and played lullabies and soothing melodies on a harp. Nailah observed that Jahi’s heart rate, which tended to be high, would lower when the harpist played. She wondered if her daughter found the songs calming…

“Move your hand,” Nailah says. Two seconds later, Jahi cocks her right wrist. “Very good!” Nailah says. “Can you move your hand again? Move your hand so we can see it. Move it hard.” Nine seconds later, Jahi flexes her forearm, turns her wrist, drops the cloth, and lifts her fingers. Her face is expressionless and still.

In another video, Nailah says, “Kick your foot.” Jahi’s purple blanket has been folded back, revealing her bare feet and ankles. After fifteen seconds, she wiggles her toes. “Try your hardest,” Nailah says. “I see you moved your toes, but you have to kick your foot.” Twenty-two seconds later, Jahi flicks her right foot upward. “Oh, I’m so proud of you,” Nailah says, leaning over the bed and kissing her cheek…

In late August, 2014, Jahi was released from St. Peter’s. Her discharge diagnosis was brain death. She moved into a two-bedroom apartment that Nailah and Marvin had rented in a colorless condominium complex near New Brunswick. They slept on an air mattress on the floor, and Jordyn, who had just moved to New Jersey, to begin first grade, slept on the couch. Jahi had the brightest room, with a large window overlooking the parking lot. Nurses, paid for by Medicaid, provided twenty-four-hour care, in eight-hour shifts. Every four hours, Nailah helped them turn her daughter’s body. One of Jahi’s most loyal nurses taped a note to the wall of her bedroom: “During your shift, interact with her,” she had written. “She does hear you! Speak clearly, softly, slowly.” She added, “No one knows if she understands, but just your comforting voice or touch should help.”..

A month after Jahi’s discharge, the International Brain Research Foundation, a neuroscience think tank that supports novel research, helped pay for Jahi to have MRI scans at Rutgers New Jersey Medical School. Calixto Machado, the president of the Cuban Society of Clinical Neurophysiology, flew to New Jersey to analyze the scans. Machado has published more than two hundred papers on disorders of consciousness and runs a symposium every four years that attracts the world’s leading scholars of brain death. He said, “Everybody was talking about Jahi—Jahi this, Jahi that—but nobody knew the neurological picture.” The fact that Jahi had begun menstruating—a process mediated by the hypothalamus, near the front of the brain—suggested to him that not all neurological functions had ceased…

Dolan sat beside Machado in the hospital as he looked at two computer screens showing images of Jahi’s head and the top of her spine. In the rare cases in which brain-dead patients are sustained by a ventilator, neurologists have reported a phenomenon called “respirator brain”: the brain liquefies. Machado said that if Jahi’s original diagnosis was correct, and she’d had no cerebral blood flow for nine months, he expected that she’d have little tissue structure in her cranial cavity, just fluid and disorganized membranes.

On the scans, Machado observed that Jahi’s brain stem was nearly destroyed. The nerve fibres that connect the brain’s right and left hemispheres were barely recognizable. But large areas of her cerebrum, which mediates consciousness, language, and voluntary movements, were structurally intact. Dolan shouted, “She’s got a brain!”

Machado also performed a test that measures the interplay between the sympathetic and parasympathetic nervous systems, a relationship that regulates states of arousal and rest. He used three experimental conditions, one of which he called “Mother talks to the patient.” Nailah stood next to her daughter without touching her. “Hey, Jahi, I’m here,” she told her. “I love you. Everyone is so proud of you.” Machado noted that Jahi’s heart rate changed in response to her mother’s voice. “This cannot be found in a brain-dead patient,” he wrote.

Three days after the scans, Dolan submitted a report by Machado to the Alameda County Coroner’s Bureau and asked it to rescind Jahi’s death certificate, so that Nailah could return to California and have Jahi treated there. The coroner and the county’s public-health department rejected the request. “Any opportunity to overturn the Court’s holding that Jahi McMath is brain dead has long expired,” their lawyers wrote.

D.Alan Shewmon, who had just retired as the chief of the neurology department at Olive View-U.C.L.A. Medical Center, read Machado’s report and wondered if Jahi had a condition, first proposed by the Brazilian neurologist C. G. Coimbra, called ischemic penumbra. Coimbra hypothesized that this brain state could lead to a misdiagnosis of brain death in patients whose cerebral blood flow was diminished enough that it couldn’t be detected by the standard tests. If blood was still flowing to parts of the brain, however slowly, then, in theory, some degree of recovery could be possible.

Shewmon has given a diagnosis of brain death to roughly two hundred people. He is measured, formal, and precise. When I asked him what he thought of the media coverage stating that Jahi would die imminently, he paused and said, “I sit back and let it play out.” He laughed, harder than I would have expected, and said nothing more.

Two months after Machado’s tests, Shewmon flew to New Jersey and visited Jahi at her apartment. He pulled a desk chair next to her bed and, with a notepad in his hand, watched her for six hours. Jahi did not respond to his instructions to move her limbs, a fact that Shewmon did not find particularly revealing. He had analyzed the videos that Nailah had recorded, and they suggested to him that Jahi was in a minimally conscious state, a condition in which patients are partly or intermittently aware of themselves and their environment. He wrote that her condition “creates a particular challenge to either disprove or verify, because the likelihood of Jahi being in a ‘responsive’ state during a random examination is small.”

After Shewmon left, Nailah took more videos. She followed Shewmon’s instructions not to touch her daughter during the filming and to begin the video outside Jahi’s room. Shewmon eventually analyzed forty-nine videos containing a hundred and ninety-three commands and six hundred and sixty-eight movements. He wrote that the movements occur “sooner after command than would be expected on the basis of random occurrence,” and that “there is a very strong correspondence between the body part requested and the next body part that moves. This cannot be reasonably explained by chance.” He noted that the movements “bear no resemblance to any kind of reflex,” and that, in one video, Jahi seemed to display a complex level of linguistic comprehension. “Which finger is the eff-you finger?” Nailah asked her. “When you get mad at somebody, which finger you supposed to move?” Two seconds later, Jahi flexed her left middle finger. Then she bent her pinkie. “Not that one,” Nailah said. Four seconds later, Jahi moved her middle finger again.

James Bernat, a neurologist at Dartmouth who helped develop the theory of brain death that formed the basis of the 1981 President’s Commission report, told me that Shewmon showed him some of the videos. “My thoughts about this are not fully formed,” he said, adding, “I’m always skeptical of videotapes, because of the videos of Terri Schiavo.” Her family had released video clips that they presented as proof of consciousness, but the videos had been edited, giving the impression that she was tracking people with her eyes, even though she was blind.* Bernat said, “I have a huge amount of respect for Alan, and if he says something, I am going to pay attention to it.” He called Shewmon “the most intellectually honest person I have ever met.”

When Shewmon was a college sophomore, at Harvard, he listened to Chopin’s Trois Nouvelles Études No. 2, in his dorm room, and the music lifted him into such a state of ecstasy that he had an epiphany: he no longer thought it possible that all conscious experience, particularly one’s perception of beauty, could be a “mere electrophysiological epiphenomenon,” he said. The music seemed to transcend “the spatial limitations of matter.” An atheist, he converted to Catholicism and studied Aristotelian-Thomistic philosophy. He went to medical school, in 1971, and then specialized in neurology, because he wanted to understand the relationship between the mind and the brain.

For the next fifteen years, he believed in and defended the notion of brain death, but in the early nineties he began to feel increasingly troubled by the concept. When he engaged in what he called “Socratic conversations” with colleagues, he saw that few doctors could confidently articulate why the destruction of one organ was synonymous with death. Usually, they’d end up saying that these patients were still living biological organisms but had lost the capacities that made them human. He thought the formulation seemed too similar to the idea of “mental death,” which the Nazis embraced after the publication, in 1920, of a widely read medical and legal text called “Permission to Destroy Life Unworthy of Living.”

“I think that from time to time he likes to remind us how talented he can be by writing something terrible.”

In 1992, Shewmon was asked to consult on the case of a fourteen-year-old boy who, after falling off the hood of a moving car, had been declared brain-dead. The boy’s family was religious and insisted that he remain on a ventilator. His physicians, certain that his heart would soon fail, acceded to his parents’ request. He survived for sixty-three days and began puberty. “This case flew in the face of everything I had been taught regarding the universality and imminence of somatic demise in brain death,” Shewmon later wrote. “It forced me to rethink the whole thing.”…

In 1997, in a paper called “Recovery from ‘Brain Death’: A Neurologist’s Apologia,” Shewmon disavowed his earlier views. He acknowledged that “dissenters from the ‘brain death’ concept are typically dismissed condescendingly as simpletons, religious zealots or pro-life fanatics,” and announced that he was joining their ranks….

In 2015, after Nailah filed her taxes, her accountant called to tell her that her submission had been rejected by the I.R.S. One of the “dependents” she’d listed was deceased. “I was, like, Oh, God, now I have to tell this guy what is going on—that she’s alive on a state level and dead on the federal level,” she said. She decided not to fight the I.R.S.; she was sure that she’d lose. “It’s not even about money,” she told me. “It’s the principle: I really have a human being that I get up and see about every day.”…

Dolan submitted video recordings of Jahi and declarations from Machado, three New Jersey doctors who had examined her, and Shewmon, who concluded that Jahi had fulfilled the requirements of brain death at the time of her diagnosis but no longer did. He wrote, “With the passage of time, her brain has recovered the ability to generate electrical activity, in parallel with its recovery of ability to respond to commands.” He described her as “an extremely disabled but very much alive teenage girl.”…

Daniel Wikler, the Harvard philosopher, told me that he guessed Jahi’s family might be suffering from “folie à famille,” a rare condition in which a delusion is shared by all members of a family. It struck me as a coherent response to the death of a child: who wouldn’t find comfort in the fantasy that the child’s will had been preserved? It seemed so intuitive that I worried I could also be investing undue meaning in gestures nearly too subtle to discern. Given the weight of the evidence, though, it seemed unlikely. Jahi’s doctors and nurses were all converts, too. On Nailah’s cell-phone recordings, which document the past four years of her daughter’s life, several different nurses can be heard congratulating Jahi for gathering the strength and commitment to move a foot or a finger…

Jordyn has learned that if she wants to have a conversation in her sister’s room she needs to stand on the same side of the bed as her mother. “Jahi doesn’t like when two people talk over her,” Nailah said. “Her heart rate shoots up.” It makes Jahi nervous and upset, Nailah said, to be treated as if she didn’t exist. “She listens to everybody’s conversations—she has no choice,” she said. “I bet she has some secrets she can tell us.” She smoothed back Jahi’s hair. “You know how sometimes, when 
you’re just sitting still, thinking, you can take yourself somewhere else? I always say, ‘Jahi, one day, I want to know everything you know and everywhere that you’ve been.’ ”

Neurological prognostication in children after cardiac arrest

Smith AE, Friess SH. Neurological Prognostication in Children After Cardiac Arrest. Pediatr Neurol. 2020 Mar 15. pii: S0887-8994(20)30089-8. doi:10.1016/j.pediatrneurol.2020.03.010. [Epub ahead of print]

Early after pediatric cardiac arrest, families and care providers struggle with the uncertainty of long-term neurological prognosis. Cardiac arrest characteristics such as location, intra-arrest factors, and postarrest events have been associated with outcome. We paid particular attention to postarrest modalities that have been shown to predict neurological outcome. These modalities include neurological examination, somatosensory evoked potentials, electroencephalography, and neuroimaging. There is no one modality that accurately predicts neurological prognosis. Thus, a multimodal approach should be undertaken by both neurologists and intensivists to present a clear and consistent message to families. Methods used for the prediction of long-term neurological prognosis need to be specific enough to identify indivuals with a poor outcome. We review the evidence evaluating children with coma, each with various etiologies of cardiac arrest, outcome measures, and timing of follow-up. ___________________________________________________________________________

From the article:

In summary, although the examination can be confounded, if performed later in a child’s hospital course, it can be helpful with prognostication of poor outcome, especially when assessing simple examination maneuvers such as pupil reactivity, respiratory drive, and motor response. However, the weaknesses of the aforementioned studies are apparent in that they are either retrospective or small prospective cohorts with a fair proportion of patients with poor outcome having withdrawal of life-sustaining therapies  and with rare multivariate analyses, thus not accounting for sedation effects. The AHA 2019 Scientific Statement on pediatric cardiac arrest recommends that early examination after return of spontaneous circulation (ROSC) be interpreted for prognostication with caution and that the predictive ability improves with serial examinations and time…

In conclusion, the studies presented in the previous sections demonstrate that SEPs can be helpful in predicting poor outcome in comatose children after cardiac arrest . However, the lack of a homogeneous pediatric cardiac population evaluated in the studies presented is a concerning weakness. Similar to the neurological examination, utilizing SEPs as a single modality for neurological prognostication after pediatric cardiac arrest is not recommended. Thus, the AHA 2019 Scientific Statement on pediatric cardiac arrest recommends the routine use of SEPs for neurological prognostication in children after cardiac arrest be done with extreme caution…

In conclusion, the aforementioned evidence supports using EEG as a postarrest modality predictor of both favorable and unfavorable outcomes at PICU or hospital discharge. The majority of quality evidence supports using background EEG features for these outcome measures. The current pediatric literature is limited by study size and retrospective study design. In 2015, the American Clinical Neurophysiology Society published a consensus statement on indications for continuous EEG in critically ill children. In this statement, continuous EEG for 24 hours is recommended to identify nonconvulsive seizures or status epilepticus in critically ill children with altered mental status after acute brain injury post-cardiac arrest. In addition, evidence is provided to recommend assessing for seizures if a critically ill child is being treated with neuromuscular blockade and at risk for seizures. This statement also mentions that EEG can aid in prognosis in children with hypoxic-ischemic injury after cardiac arrest. The AHA Pediatric Advanced Life Support 2015 guidelines state that EEG recordings done within seven days after ROSC can be helpful in prognostication at time of hospital discharge but should not be the only modality used…

In summary, MRI and HCT can be useful in prognostication after pediatric cardiac arrest. The current literature is limited by study size, variable timing of imaging, modalities of imaging, and inconsistency of the findings evaluated in each study. Further work should focus on comparison of regional injury patterns with whole-brain analysis for prognostication. Trends in the aforementioned literature suggest that regional injury in the basal ganglia and deep gray and occipital lobes is associated with poor outcomes. The AHA 2019 Scientific Statement on pediatric cardiac arrest recommends HCT as a useful tool to identify treatable intracranial injury, but evidence is insufficient to support use for prognostication, whereas brain MRI with DWI sequences done in the first three to seven days after ROSC may be useful to supplement other prognostication criterion…

Optimal prediction of neurological outcomes after pediatric cardiac arrest requires a multimodal approach incorporating the available data including cardiac arrest characteristics, neurological examination at least 24 hours from ROSC or normothermia, EEG background features, SEP responses, and neuroimaging. Advanced techniques including quantitative measures on EEG and MRI may provide new objective data from modalities that have been measured qualitatively previously. This review also highlights the lack of standardization in outcome measures and timing of assessments, which will be essential for moving the field of pediatric cardiac arrest forward.

A single shake is dangerous

Babies are at far greater risk of brain damage than previously thought.

Even activities that seem innocent, like a quick run in a jogging stroller, can inflict abusive head trauma. And head injuries often go entirely undetected, so parents unwittingly repeat the same harmful behaviors over and over again.

These conclusions, which come from a new study I co-authored in the Journal of Pediatric Neurology, must be used to better educate new parents and inform manufacturers as they design car seats, safety helmets, and the like.

Abusive head trauma, or AHT, is typically referred to as --"shaken baby syndrome" -- the consequence of awful, deliberate abuse. Every year, an estimated 1,300 infants suffer this brain trauma. Roughly one in four tragically dies. Of those who survive, about 80 percent develop lifelong disabilities.

Of course, the overwhelming majority of parents would never intentionally harm their children. But, as our new research makes clear, it's possible to inflict AHT without even knowing it.

There are several reasons why this unsettling truth is just now coming to light. For starters, it's difficult to diagnose AHT. Some cases result in noticeable injuries, including bone fractures. But others result in far milder symptoms, such as fussiness. Many victims of AHT show no signs of trauma whatsoever. 

Plus, studying the biomechanics of AHT -- what physically occurs inside a child's skull when his or her head moves back and forth rapidly -- presents its own challenges. After all, there's no ethical way to observe or replicate such injuries in a scientific setting.

But thankfully, there's another way to study the problem. My colleagues and I used computer models to simulate the biomechanics of AHT. Specifically, we looked at how the cerebrospinal fluid cushions the brain when a child is shaken repeatedly.

What our models revealed is startling. Even at the lowest frequency we studied -- two shakes per second -- a single shake is dangerous. More troubling still, after that initial shake, the cerebrospinal fluid stops cushioning the brain altogether, causing the child’s brain to collide with the skull wall.

In other words, it doesn't take a violent act of frustration to damage a baby's brain. Something as ordinary as playfully tossing a child in the air or jogging with a baby could be enough to inflict severe head trauma. 

Of course, additional research is needed to develop even more precise AHT simulations. But our conclusions suggest several strategies for preventing head trauma in young children.

The first is simple -- parents must avoid any activity that shakes their infant's head even once, however harmless it might seem.

Just as important, designers should rely on biomechanical models when designing items like car seats, strollers, and other baby products. In 2018 alone, U.S. emergency rooms treated children under five for 59,000 injuries related to nursery products -- such as walkers, bouncer seats, and baby swings. Strollers were involved in 8,200 of those injuries. And across all of these incidents, the child's head was the most commonly injured part of the body.

Of course, faulty design didn't cause all of these accidents. But better-constructed products based on the latest biomechanics research could go a long way toward reducing head injuries in young children. Such research might reveal that jogging strollers require better shock absorbers, or that car seats should include more protective headgear.

At the very least, researchers should use biomechanical simulations to evaluate the safety of existing baby products. The results might surprise them -- newer products are not necessarily safer than older ones. In February, biomechanics researchers at Duke University found that World War I-era combat helmets provided better protection from certain kinds of explosions than current military helmets. Imagine what researchers might find if they subjected modern baby products to the same scrutiny.

The latest biomechanics research reveals that babies are far more vulnerable to head trauma than previously thought. It's time to minimize this trauma -- or eliminate it -- by using these findings to better educate new parents and design safer baby products.

Milan Toma, Alfonso Dehesa-Baeza , Rosalyn Chan-Akaley, Paul D. H. Nguyen, Hallie Zwibel. Cerebrospinal Fluid Interaction with Cerebral Cortex during Pediatric Abusive Head Trauma.  Journal of Pediatric Neurology.  DOI: 10.1055/s-0040-1708495

Abusive head trauma is the leading cause of fatal brain injuries in children younger than 2 years. It is a preventable and severe form of physical child abuse often linked to the forceful shaking of an infant or toddler. Victims of abusive head trauma can suffer permanent neurological damage, resulting in developmental delay and disability. The long-term effects of abusive head trauma are difficult to diagnose and predict. In this model, we use a high-order finite element method paired with the most comprehensive and current head/brain model and next-generation smoothed particle hydrodynamics. This is one of the first fluid–structure interaction frameworks that uses fluid material properties to represent the cerebrospinal fluid (CSF) while including all major anatomical features of the brain. The interaction of CSF with the brain cortex during abusive head trauma is demonstrated during multiple shaking cycles. A comprehensive and precise model that calculates for the role of CSF in neurological trauma will be useful both in the prevention and treatment of abusive head trauma and the determination of prognosis and patient outcomes.

Friday, May 15, 2020

Lisdexamfetamine as treatment for paroxysms in KCNMA1 mutation

An almost 8 years girl with a KCNMA1 mutation (chr10:g.78651467T>C(GRCh37) c.2996A>Gp.Asn999Ser) would have countless daily paroxysms with loss of tone and gradual collapse.  Efforts to treat these with a variety of medications were unsuccessful.  The medications included levetiracetam, oxcarbazepine, clonazepam, imipramine, acetazolamide and ethosuximide.  The patient’s mother through a KCNMA1 parent network heard of a boy with evidently an identical mutation who at 9 years of age was prescribed lisdexamfetamine dimesylate (Vyvanse) for attention deficit symptoms.  Concurrent with lisdexamfetamine administration, there was a remarkable abolition of his paroxysmal episodes.  This had continued for 10 years. When lisdexamfetamine effect wears off, the episodes promptly recurred.

Upon hearing of this, I asked the mother whether she would be interested in  trial of lisdexamfetamine therapy for her daughter.  At first she demurred, but, after discussing it with her daughter, she gave a try with lisdexamfetamine at a 10 mg dosage.  That day her daughter had 6 episodes instead of “hundreds”.  The next day it was 4 episodes.  On the third day, no episodes occurred, which had never previously happened.  Subsequently, the lisdexamfetamine dose was increased to 20 mg.  The patient is episode free during the day. In the evening, when lisdexamfetamine effect wore off, episodes would again occur.

The mother is aware of one other child treated successfully with lisdexamfetamine and another child, evidently with evidence of significant cerebral disease, who did not benefit . The mutation here is a gain of function mutation.  The mother suggests that only patients with KCNMA1 gain of function mutation seem to benefit from lisdexamfetamine.


Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study

Schiavoni S, Spagnoli C, Rizzi S, Salerno GG, Frattini D, Pisani F, Fusco C. Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study. Dev Med Child Neurol. 2020 Apr 10. doi: 10.1111/dmcn.14547. [Epub ahead of print]


To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit.

We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]).

Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes.

We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations.

A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.

Courtesy of:

Tuesday, May 12, 2020

Phenotypic and imaging spectrum associated with WDR45

Laura A. Adang, Amy Pizzino, Alka Malhotra, Holly Dubbs, Catherine Williams, Omar Sherbini, Anna-Kaisa Anttonen, Gaetan Lesca, Tarja Linnankivi, Chloé Laurencin, Matthieu Milh, Charles Perrine, Christian P. Schaaf, Anne-Lise Poulat, Dorothee Ville, Tanner Hagelstrom, Denise L. Perry, Ryan J. Taft, Amy Goldstein, Arastoo Vossough, Ingo Helbig, Adeline Vanderver.  Phenotypic and imaging spectrum associated with WDR45.  Pediatric Neurology, in press. 

Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5 (NBIA5). Global developmental delay is seen at an early age with a slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.

We present 17 new cases and reviewed 106 reported cases of NBIA5. Detailed information related to developmental history and key time to event measures was collected.

Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. While most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted half of our cohort and was associated with an older age of image acquisition, while myelination abnormalities were associated with a younger age.

WDR45 is a progressive and evolving disorder, which is often delayed in diagnosis. Developmental delay and seizures predominate early childhood, followed by a progressive decline of neurologic function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

Sunday, May 10, 2020

Neonatal extra-axial hemorrhage 3

At 3 ½ years of age, this boy was experiencing ponderous medical problems.  He was admitted for somnolence and lethargy.  At baseline he was bradycardic and his temperature was 36.5.  He had undergone a right frontotemporal parietal craniotomy for right functional hemispherectomy.  He had been treated with ketogenic diet and a vagal nerve stimulator.  He was receiving levetiracetam, valproate, oxcarbazepine and phenobarbital, as well as gabapentin (probably for irritability, not epilepsy).  Previous medications had included lacosamide and topiramate.  There had been numerous recent admissions for status epilepticus.

An electroencephalogram 5 months earlier had shown multifocal epileptiform discharges in the left hemisphere and right posterior quadrant, as well as suppression of the right hemisphere and slowed posterior dominant rhythm. 

Laboratory studies on presentation included sodium 131, potassium 6.0, BUN 21, bicarbonate 22,  ALT 13, AST 51, albumin 2.5. and ammonia 93.  White blood cell count 16.0, platelets 312, hematocrit 40 mg. Phenobarbital level was 34,  levetiracetam 14.8, valproate 53, free valproate (I didn’t order it!) 12 and oxcarbazepine 20.

A quick brain MRI showed mild interval increase in caliber of the left lateral ventricle, raising
possibility of mild hydrocephalus. There was unchanged mild periventricular T2 FLAIR
hyperintensity along the left lateral ventricle. There was no new abnormal brain
parenchymal attenuation.  There was unchanged postoperative appearance of right hemispherectomy.

                                                         Coronal T2 Haste imaging

Shortly after admission, the patient had a fever of 40.3, which was treated aggressively with antibiotics.  No focus of infection was identified.  The patient was oliguric and fluid challenges did not increase urine output.  A renal ultrasound showed mild left hydronephrosis. He was having increased oxygen requirement from his baseline, most likely secondary to fluid overload from renal failure. CXR did not show pneumonia. He was placed on the hospital ventilator at family request to see if this would improve things. His oxygen requirement remained the same and his end tidal then also started to climb. He also progressively took less of his own spontaneous breaths over the ventilator rate until he was riding the ventilator rate only. Ventilatory support was tapered and discontinued. He was deemed to have septic shock and acute renal failure.

The family had discussed with the PICU team their desire to keep patient comfortable and treat reversible causes, but that if at any point the process seemed irreversible, that they would want to know.  When the patient became hypotensive, the family chose to take him back to hospice.  They understood that with renal failure, he wouldn't tolerate fluid resuscitation and that continued fluid overload would cause worsening respiratory status.  They also did not want to risk increased cardiac stress with vasopressors, since he was already hyperkalemic and acidotic.  They wanted to be able to transfer him while he was still stable and not risk a sudden cardiac event.  It was very important to them that he did not pass away in the hospital if possible.

The patient passed away nine days later in hospice.

Friday, May 8, 2020

Using the common data model to identify antiseizure drug-related adverse reactions

Choi SA, Kim H, Kim S, Yoo S, Yi S, Jeon Y, Hwang H, Kim KJ. Analysis of antiseizure drug-related adverse reactions from the electronic health record using the common data model. Epilepsia. 2020 Apr;61(4):610-616. doi:10.1111/epi.16472.


Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD‐related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital.

We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications.

From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group.

The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD‐related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

The information on the appearance and frequency of side effects is essential for all drugs, especially those used for an extended period. Although patients generally experience relatively mild abnormalities, sometimes they can suffer life-threatening severe side effects. However, side effects are assessed only in a very limited number of patients in most cases, such as pre-marketing clinical trials or post-marketing investigations. It is nearly impossible to investigate all patients who use drugs.

The research team, led by Professors Hwang Hee, Kim Hun-min, and Yoo Soo-young, analyzed the big data of medical information systems that have already been de-identified and structured, the hospital said in a news release on Wednesday.

They used the Observational Medical Outcomes Partnership (OMOP)-CDM database of about 170 million patients for the study. OMOP-CDM is a data model that transforms electronic medical records information, such as different terms and formats for each medical institution, into a standardized structure.

The study used data from blood tests conducted during the period of drugs and anticonvulsants used by 1,344 out of around 5,000 patients treated at the hospital’s Department of Pediatric Neurology, specializing in epilepsy, from 2003 to 2017.

Based on the results of blood tests conducted during the five most commonly used anticonvulsants, the research team confirmed abnormalities such as anemia, thrombocytopenia, leukopenia, hyponatremia, thyroid dysfunction, and liver dysfunction.

Using the CDM data, the researchers could analyze the overall information of abnormalities in blood tests due to anticonvulsants in all children with epilepsy, the hospital said. Furthermore, they confirmed the exact prevalence of side effects that could be caused by the drugs already known, as well as the previously unknown side effects.

"We were able to complete the study in months with the CDM model while similar observation of drug side effects typically usually requires more than a year," Professor Hwang said.

The study was meaningful as it showed the possibility of replacing some of the existing post-marketing surveys in a short period with less expense if it is spread to multi-agency research in the future due to the nature of CDM, he noted.

Professor Kim also said, “CDM model is fast and accurate, but careful design is also significant because there are some points that can be missed out in the process of specifying search conditions.”

Sunday, May 3, 2020

Sirolimus treats epilepsy in pediatric patients with tuberous sclerosis

Wen He, Jian Chen, Yang-Yang Wang, Xiao-Mei Luo, Xiao-Qiao Chen, Li-Ping Zou.  Sirolimus Improves Seizure Control in Pediatric Patients with Tuberous Sclerosis: a Prospective Cohort Study.  Seizure. Published:April 26, 2020DOI:

Sirolimus has a significant effect on seizures associated with tuberous sclerosis
Early use of sirolimus to control seizures can bring long-term benefits
The overall tolerability of sirolimus is acceptable


This study aimed to analyze the therapeutic effect of sirolimus on seizures in pediatric patients with tuberous sclerosis.

We first compared the efficacy of controlling seizures in all patients after they had taken sirolimus for one year, and then we performed a subgroup analysis based on whether the administered antiepileptic drugs were changed to determine whether the efficacy was associated with changes of antiepileptic drugs.

A total of 91 eligible children were enrolled. The response rate was 78.0% (71/91), and 47.2% (43/91) of all patients were became seizure-free. The improvement in seizure control before and after treatment with sirolimus was significant ( p < 0.001). In the AEDs unaltered group, 34 were responders (34/45, 75.6%, 95% CI 17.4–88.3), of which 24 were seizure-free (24/34, 70.6%). In the AEDs-altered group, 37 were responders (37/46, 80.4%, 95% CI 56.7–88.1), of which 19 were seizure-free (19/37, 51.4%). There was no significant difference between the two groups for reductions in rate of seizure frequency ( p = 0.308). In the patients with refractory epilepsy, treatment with sirolimus was also effective ( p = 0.01). Logistic regression analysis showed that age was an important factor affecting outcome of epilepsy ( p = 0.003, 95% CI 2.05–38.31). No Grade 3 or 4 adverse events were noted during the follow-up.

Sirolimus has a significant effect on seizures associated with tuberous sclerosis complex (TSC), with no or only moderate adverse events after long-term administration. Sirolimus could be used as the first-line medication for pediatric patients with TSC-associated epilepsy.

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