Saturday, February 29, 2020

Intussusception encephalopathy

Gayle T. Case 3: Sudden Altered Mental Status in an 11-month-old Boy. Pediatr Rev. 2020 Feb;41(2):88-89.

An 11-month-old boy presents to an emergency department (ED) after multiple witnessed episodes that were concerning for seizures. His parents note that he was in his normal state of health last night but this morning started becoming increasingly fussy. He then developed a blank stare and went limp. This happened 1 more time where he was seen to have perioral cyanosis. There were no convulsions, noted abnormal movements, or incontinence. He was quiet for a few minutes after this occurred but started to cry afterward. He was then taken to the community ED. He again developed a blank stare and went limp, which was witnessed by the care team on arrival in the ED. The family denies any fever or diarrhea, although he has had 2 episodes of nonbilious, nonbloody emesis after his staring episode. There was no witnessed ingestion or concern for nonaccidental or accidental trauma. He had been taking fluids well, with good urine output. There are no sick contacts at home, he does not attend child care, and there has been no recent travel. He is not taking any medication at home, has age-appropriate development, has not been hospitalized, and has received all of his vaccines.

Physical examination reveals a drowsy-looking pale infant with normal vital signs. The patient is circumcised. He was noted to be hypotonic during the episodes, but his neurologic examination findings are now normal. All other physical examination findings are normal.

Laboratory results are significant for a mild leukocytosis (white blood cell count, 15,200/μL [15.2×109/L]) and mild thrombocytosis with a platelet count of 473×103/μL (473×109/L). He had normal findings on a comprehensive metabolic panel, urinalysis, and urine toxicology screen looking for acetaminophen or other drugs he could have gotten into in the home. Blood and urine cultures were performed because there was concern that he could be in early sepsis, and the results are pending. Head computed tomography and chest radiography were normal. The diagnosis is determined after additional studies.

The patient was transferred to a tertiary children’s hospital for evaluation by pediatric neurology. At the time of transfer the differential diagnosis included a new seizure disorder, encephalitis, unwitnessed ingestion, and head injury. On transfer, the receiving ED physician decided to order abdominal radiography and ultrasonography. The ED physician wanted to expand the differential diagnosis beyond neurologic complaints because the infant was now no longer having neurologic symptoms but was still acting fussier than usual, per mom. The combination of emesis, fussiness, and that the child was afebrile made the provider concerned for the diagnosis of intussusception. Ultrasonography showed ileocolonic intussusception extending to approximately the level of the proximal transverse colon. The boy then went directly to interventional radiology for reduction, which was successful. The patient was found to return back to baseline behavior and started being playful and interactive. A few hours later he surprisingly again became increasingly fussy, so was imaged again with ultrasonography. This was secondary to the concern that intussusception could have recurred, which happens in approximately 10% of all intussusception cases. His repeated ultrasonography showed that the intussusception was resolved. He was observed overnight and was able to go home the following morning, tolerating a regular diet…

Lessons for the Clinician

Patients usually present with intermittent, crampy abdominal pain, sometimes accompanied by bringing the knees to the chest.

The triad that is considered classic—intermittent colicky pain, currant jelly stool, and emesis—is a late finding of this diagnosis.

This is an important diagnosis to think about particularly in children and infants who have an unexplained change in their mental status, particularly those younger than 1 year.

Children younger than 1 year are also more likely to present with emesis and heme-positive or clearly bloody stools.

Importantly, infants can also present without any accompanying signs of abdominal pain and typically will be afebrile.

Goetting MG, Tiznado-Garcia E, Bakdash TF. Intussusception encephalopathy: an underrecognized cause of coma in children. Pediatr Neurol. 1990 Nov-Dec;6(6):419-21.

Intestinal intussusception is a common cause of bowel obstruction in infancy and early childhood. Typically the presenting signs and symptoms are referable to the abdomen. On occasion the most prominent presenting feature is depressed level of consciousness. We describe 3 patients who presented with coma associated with intussusception.

Aygün F, Aydın PÖ, Emre Ş, Uzunoğlu SŞ, Saltık S, Çam H. A rare case with encephalopathy. Turk Pediatri Ars. 2016;51(3):169–172. Published 2016 Sep 1. doi:10.5152/TurkPediatriArs.2016.3460

The patient whom we presented in this article was referred to us, because his neurological picture deteriorated and the etiology could not be elucidated. At the time of admission, the airway, respiration and circulation were assessed rapidly and the vital signs were monitorized. No prominent pathology was described in the history except for previous upper respiratory tract infection. His hemodynamic status was stable and body temperature was normal. He was followed up in another center before being internalized in intensive care unit and the laboratory tests and imaging methods performed there revealed no pathology. When a palpable mass was found on physical examination, urgent abdominal ultrasonography was performed to elucidate the etiology and ileocolic invagination was detected. After sugery, the patient’s consciousness returned to normal completely and additional investigation or treatment was not required.

Deutetrabenazine in Tourette Syndrome

Teva Pharmaceuticals announced that the phase 2/3 ARTISTS 1 and phase 3 ARTISTS 2 trials of deutetrabenazine in pediatric patients with moderate to severe Tourette Syndrome did not meet the primary end point.

ARTISTS 1 and ARTISTS 2 are phase 3, multicenter, randomized, double-blind, placebo-controlled studies that assessed the efficacy and safety of deutetrabenazine in 277 pediatric patients aged 6 to 16 years with moderate to severe Tourette Syndrome. Patients were randomized 1:1 to receive either deutetrabenazine or placebo for 8 weeks (ARTISTS 2) or 12 weeks (ARTISTS 1). The primary end point for both studies was the change in the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS).

Findings from both studies demonstrated that deutetrabenazine failed to meet the primary end point of reduction in motor and phonic tics. To date, the most commonly reported adverse events were headache, somnolence and fatigue. The safety profile of deutetrabenazine was consistent with that seen in previous studies and no new safety signals were identified.

Thursday, February 27, 2020

ECHS1 mutations in Leigh disease

Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J. ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain. 2014 Nov;137(Pt 11):2903-8. doi:10.1093/brain/awu216.

Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

Bianca Saez--A Tourette syndrome story

No one forgets an encounter with Bianca Saez. When Tara Brown first met her 11 years ago, Bianca was 16 and had the worst case of Tourette Syndrome doctors had even seen. She was a hostage to uncontrollable, violent tics and sudden outbursts of extraordinary expletives. Bianca lived at the mercy of her troubled mind until doctors performed radical brain surgery. Instantly, and for two miraculous weeks, she was free of her Tourette’s. But then, cruelly, infections set in and the operation had to be reversed. Today, Bianca still suffers severely from Tourette’s, but she has learnt to navigate the near impossible. She has found love, independence and happiness… even though she still swears like a trooper.

Update 12/19/23

At just 16 years of age, Bianca Saez had the worst case of Tourette Syndrome doctors had ever seen in Australia – if not the world.

First diagnosed at the age of three, the sweet young girl's condition meant that at any time – with no given notice – she was at the mercy of uncontrollable fits, violent tics and sudden outbursts of extraordinary expletives.

Bianca would punch, scratch and attack not only her own body but also her loving family. She would scream profanities at passers-by, and with age, her condition simply continued to get worse.

In 2008, supported by her devoted parents John and Leanne, Bianca bravely sat down with 60 Minutes reporter Tara Brown to share her brutal struggle for self-control in the hope it would bring some understanding to the confronting condition.

"I want to get rid of my tics, and have a better life," an emotional Bianca told 60 Minutes.

"I hate hitting my mum. I hate hitting everybody. If I had one wish I would take that away."

As 60 Minutes revealed, Bianca's sudden violent outbursts had seen every wall in her battered family home punched in, tiles ripped from the bathroom and furniture destroyed.

Much to the heartbreak of her parents, Bianca was forced to live at an adolescent mental health centre in Brisbane due to her uncontrollable behaviour. She couldn't attend normal school and had trouble making any kind of normal teenage friendships.

"Seeing her like this – it's the last thing a parent wants for their perfect child," a tearful Leanne told reporter Tara Brown.

"When I had Bianca, I just looked at her and couldn't believe that something so perfect - I made that. And then for something to go wrong is a nightmare. I never want that for my child, and I love her so much."

The Saez family were truly at their wit's end. And their story broke the nation's heart.

Since 2008, 60 Minutes' story with Bianca has been viewed more than 27 million times.

Her brutal struggle for self-control touched the hearts of millions.

60 Minutes was inundated with not just praise for brave Bianca, but requests for updates on her condition in the years to follow. And this week on 60 Minutes, Bianca is back.

"All I want to do is create awareness," a now 27-year-old Bianca tells Tara Brown in a preview of this week's report.

"What doesn't kill me makes me stronger."

As 60 Minutes first reported in 2008, Bianca was at the mercy of her own troubled mind until doctors performed radical brain stimulation surgery.

The operation was the first of its kind on a Tourette's patient in Australia and promised to reset the misbehaving brain cells that caused Bianca's severe condition.

For the two miraculous weeks that followed the surgery, Bianca was Tourette's free, finally able to walk without hitting and talk without swearing.

For the two weeks after surgery, Bianca was Tourette's free, finally able to walk without hitting and talk without swearing. 

"I'm so grateful for this," she told Tara Brown in 2008.

"I can't believe how much I'm grateful for having this operation because it's changed my whole entire life and I'm so proud of myself for doing it."

But tragically, in the months after 60 Minutes finished filming, a staph infection set in and ultimately led to the removal of the Bianca's changing electrodes.

Both Bianca and her doctors were determined to persevere, and over the past decade further attempts were made to eradicate her Tourette's.

Eleven years after her first 60 Minutes interview, Bianca now tells Tara Brown she has abandoned the hope for further radical brain stimulation surgery. She has accepted that there will be no cure for her condition. But despite it all, she is incredibly happy.

As Tara Brown shares this Sunday on 60 Minutes, Bianca is not just surviving but thriving with her Tourette's. A truly inspirational woman with a powerful message to share.

Wednesday, February 26, 2020

Predictors of cognitive development in children with neurofibromatosis type 1 and plexiform neurofibromas

Hou Y, Allen T, Wolters PL, Toledo-Tamula MA, Martin S, Baldwin A, Reda S, Gillespie A, Goodwin A, Widemann BC. Predictors of cognitive development in children with neurofibromatosis type 1 and plexiform neurofibromas. Dev Med Child Neurol. 2020 Feb 12. doi: 10.1111/dmcn.14489. [Epub ahead of print]


To describe the cognitive development of children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas, and identify predictors of cognitive development.

Participants included 88 children with NF1 and plexiform neurofibromas (50 males, 38 females, aged 6-18y, mean=12y, SD=3y 7mo) on a natural history study at the National Cancer Institute. Neuropsychological assessments (e.g. IQ, academic achievement, attention, and executive functioning) were administered three times over 6 years.

Relative to normative peers, the total sample of children with NF1 and plexiform neurofibromas demonstrated significantly lower scores in most cognitive domains and decreasing z-scores over time in math, writing, inhibitory control, and working memory. Children who had parents with (vs without) NF1 were more likely to experience decreased z-scores in performance IQ, reading, writing, attention, and working memory. Higher (vs lower) parental education was related to higher levels of IQ, math, reading, and cognitive flexibility and a slower decrease in math z-scores. Children's sex and the number of NF1 disease-related complications were not related to most cognitive outcomes.

Children with NF1 and plexiform neurofibromas are at high risk for cognitive difficulties and declining z-scores in various domains of cognitive functioning over time. The findings highlight the need for a better understanding of the within-group differences in these children and their need for individualized educational plans.

Math, writing, inhibitory control, and working memory scores decreased over time. The proportion of children with clinically significant cognitive deficits increased over time. Parental neurofibromatosis type 1 and low education were related to greater cognitive difficulties in children.

Courtesy of:

Tuesday, February 25, 2020

A systematic review and network meta-analysis of pharmacologic treatments for pediatric migraine prophylaxis

Locher C, Kossowsky J, Koechlin H, Lam TL, Barthel J, Berde CB, Gaab J, Schwarzer G, Linde K, Meissner K. Efficacy, Safety, and Acceptability of Pharmacologic Treatments for Pediatric Migraine Prophylaxis: A Systematic Review and Network Meta-analysis. JAMA Pediatr. 2020 Feb
10. doi:10.1001/jamapediatrics.2019.5856. [Epub ahead of print]


Migraine is one of the most common neurologic disorders in children and adolescents. However, a quantitative comparison of multiple preventive pharmacologic treatments in the pediatric population is lacking.

To examine whether prophylactic pharmacologic treatments are more effective than placebo and whether there are differences between drugs regarding efficacy, safety, and acceptability.

Systematic review and network meta-analysis of studies in MEDLINE, Cochrane, Embase, and PsycINFO published through July 2, 2018.

Randomized clinical trials of prophylactic pharmacologic treatments in children and adolescents diagnosed as having episodic migraine were included. Abstract, title, and full-text screening were conducted independently by 4 reviewers.

Data extraction was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis network meta-analysis guidelines. Quality was assessed with the Cochrane Risk of Bias tool. Effect sizes, calculated as standardized mean differences for primary outcomes and risk ratios for discontinuation rates, were assessed in a random-effects model.

Primary outcomes were efficacy (ie, migraine frequency, number of migraine days, number of headache days, headache frequency, or headache index), safety (ie, treatment discontinuation owing to adverse events), and acceptability (ie, treatment discontinuation for any reason).

Twenty-three studies (2217 patients) were eligible for inclusion. Prophylactic pharmacologic treatments included antiepileptics, antidepressants, calcium channel blockers, antihypertensive agents, and food supplements. In the short term (<5 months), propranolol (standard mean difference, 0.60; 95% CI, 0.03-1.17) and topiramate (standard mean difference, 0.59; 95% CI, 0.03-1.15) were significantly more effective than placebo. However, the 95% prediction intervals for these medications contained the null effect. No significant long-term effects for migraine prophylaxis relative to placebo were found for any intervention.

Prophylactic pharmacologic treatments have little evidence supporting efficacy in pediatric migraine. Future research could (1) identify factors associated with individual responses to pharmacologic prophylaxis, (2) analyze fluctuations of migraine attack frequency over time and determine the most clinically relevant length of probable prophylactic treatment, and (3) identify nonpharmacologic targets for migraine prophylaxis.

Courtesy of:

Epilepsy patients taking newer AEDs may not benefit from routine drug monitoring

Aícua-Rapún I, André P, Rossetti AO, Ryvlin P, Hottinger AF, Decosterd LA, Buclin T, Novy J. Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment. Ann Neurol. 2020 Jan;87(1):22-29. doi:10.1002/ana.25641.


Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy.

We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints.

A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit.

This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.

Doing routine monitoring of drug levels of the newer antiepileptic drugs (AEDs) may not lead to better seizure control or treatment tolerance for patients with epilepsy, according to a randomized trial from Switzerland...

“The main finding is that despite the variable bioavailability of the newer- generation AEDs, the systematic monitoring of their plasma levels does not bring a tangible benefit for patients,” said Jan Novy, MD, PhD, the study supervisor, neurologist, and senior lecturer at the University of Lausanne.

However, therapeutic drug monitoring of the newer AEDs is advisable in certain situations, such as when the patient is pregnant or there is a suspicion the patient is not taking the medication as prescribed, Dr. Novy told Neurology Today in an interview.

The question of whether therapeutic drug monitoring of newer AEDs is justified has been debated in part because routine monitoring was done for older-generation AEDs, including phenytoin, carbamazepine, phenobarbital, and valproate, and some clinicians have just continued the habit.

“The relationship between AED plasma levels and clinical effect has been well established for those agents, allowing the definition of reference ranges that are widely accepted,” the paper said.

Newer-generation AEDs, in comparison, have much broader therapeutic ranges, and there is not as much clear evidence of a correlation between plasma levels of the drug and clinical response, according to the new paper.

The utility of therapeutic drug monitoring for newer AEDs was never assessed in a controlled trial, the study authors wrote, adding: “Its usefulness tends, however, to be accepted and even recommended for certain situations such as pregnancy.”...

The study authors cautioned that despite that general conclusion, systematic monitoring is warranted for pregnant women, as well as cases where compliance is an issue, the patient has renal or hepatic dysfunction, or there is possible drug interaction...

Shawniqua Williams Roberson, MD, assistant professor of neurology at Vanderbilt University Medical Center, said the study findings fit with her clinical practice, noting “I don't think that getting levels systematically every three months is useful.”

Dr. Williams Roberson said she does tend to get a blood reading if a patient changes doses or starts a new drug or if she suspects the patient is noncompliant. But she considers the blood level to be a baseline number that can serve as a reference point going forward if there is a need to switch drugs or dosage due to clinical symptoms rather.

Dr. Williams Roberson said most new AEDs have very broad therapeutic ranges and a dosage that might work for one patient may not work for another.

“Although there are general therapeutic guidelines (for AEDs), different patients respond differently,” Dr. Williams Roberson said. “With that in mind, I am more interested in an individual response to an individual dose.” She said putting too much emphasis on blood levels could mean “unnecessarily adjusting a dose based on what the blood level comes out to be.” She prefers to take time to see how a patient responds and adjusts to a given dose or drug...

Pavel Klein, MD, FAAN, founder and director of the Mid-Atlantic Epilepsy Center In Bethesda, MD, said the new study echoes an epilepsy treatment mantra he learned in residency that “you treat the patient, not blood levels.”

“The study confirms the general clinical practice impression that usefulness of getting drug levels on the newer AEDs is limited when you compare a patient against the general population, especially given the broad therapeutic ranges of the newer AEDs, which are so broad as to be virtually meaningless.”

He said the new AEDs are not like the blood-thinning drug warfarin, for instance, where having too little or too much of the drug circulating in the body can be dangerous.

But Dr. Klein cautioned against drawing sweeping conclusions about the new study because most of the study participants were taking just one of two AEDs, lamotrigine and levetiracetam, and several newer AEDs were not evaluated at all.

He said he finds that getting a baseline reading on an AED can be revealing if it is used to “compare a patient to him or herself” should there be a change in how a patient is faring. Getting a blood level can also be useful in the case of medication non-compliance or to check for possible drug interactions if a patient is taking a number of different drugs for various conditions, he said...

Page B. Pennell, MD, professor of neurology at Harvard Medical School and director of epilepsy research at Brigham and Women's Hospital, said that while she generally agreed with the overall study findings, “I hope people, don't throw out the baby with the bath water.”

Dr. Pennell specializes in women with epilepsy who are pregnant or wanting to become pregnant and said that in those cases getting the patient's AED blood level does have value in helping determine optimal treatment. She said oral contraceptives can also influence AED drug levels, so getting a baseline reading can likewise be informative.

Another instance where she likes getting a baseline reading is with older people with late-onset epilepsy, defined as over the age of 50 or 60. She said those older patients might require a much lower dose of drug and yet they may have higher circulating levels of the drug than would be expected.

Dr. Pennell said that while doctors draw on their collective clinical experience in making prescribing decisions, it's important to consider each patient as an individual.

“I may have one patient who at 2.5 (mg/L) of lamotrigine is seizure free, but another patient may need a level of 6 to 8,” she said. “The driving principle needs to be what is right for this patient?”

Saturday, February 22, 2020

Pelletier verdict

Boston Children's Hospital wasn't medically negligent in its treatment of a Connecticut teen who spent nearly a year in state custody after doctors suspected her parents of medical child abuse, a jury in Boston concluded Thursday.

The verdict in the medical malpractice lawsuit brought by the family of Justina Pelletier capped a high profile dispute that drew national media attention and sparked a broader debate over parental rights.

Doctors and Pelletier's parents disagreed on whether the cause of her numerous health problems, which included an inability to walk, talk or swallow, were true medical ailments, as her parents maintained, or were largely psychological.

The Suffolk County jury reached its verdict after less than six hours of deliberating Thursday.

The trial spanned five weeks and centered on whether Pelletier's parents were unfairly barred from their daughter's treatment and whether Pelletier's separation from her family was detrimental to her health.

"The jury's decision affirms what Boston Children's Hospital has always believed: that our clinicians provided Justina Pelletier high quality, compassionate care, and always acted in the best interest of her health and well-being," the hospital said in a statement.

Pelletier's lawyers didn't respond to an email seeking comment Thursday.

Thursday, February 20, 2020

The genetics and epigenetics of 22q11.2 deletion syndrome

Qiumei Du, M. Teresa de la Morena and Nicolai S. C. van Oers. The Genetics and Epigenetics of 22q11.2 Deletion Syndrome.  Front. Genet., 06 February 2020 |

Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chromosome 22, leading to a haploinsufficiency of ~106 genes, which comprise coding RNAs, noncoding RNAs, and pseudogenes. The consequent haploinsufficiency of many of the coding genes are well described, including the key roles of T-box Transcription Factor 1 (TBX1) and DiGeorge Critical Region 8 (DGCR8) in the clinical phenotypes. However, the haploinsufficiency of these genes alone cannot account for the tremendous variation in the severity and penetrance of the clinical complications among those affected. Recent RNA and DNA sequencing approaches are uncovering novel genetic and epigenetic differences among 22q11.2del patients that can influence disease severity. In this review, the role of coding and non-coding genes, including microRNAs (miRNA) and long noncoding RNAs (lncRNAs), will be discussed in relation to their bearing on 22q11.2del with an emphasis on TBX1.

Tuesday, February 18, 2020

Adjunctive perampanel in pediatric patients

Fogarasi A, Flamini R, Milh M, Phillips S, Yoshitomi S, Patten A, Takase T, Laurenza A, Ngo LY. Open-label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic-clonic seizures. Epilepsia. 2020 Jan;61(1):125-137. doi: 10.1111/epi.16413.


Study 311 (NCT02849626) was a global, multicenter, open-label, single-arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once-daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic-clonic seizures [FBTCS]) or generalized tonic-clonic seizures (GTCS).

In the 311 Core Study, a 4-week Pre-treatment Period (Screening/Baseline) preceded a 23-week Treatment Period (11-week Titration; 12-week Maintenance) and 4-week Follow-up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days from Baseline (Treatment Period), and 50% responder and seizure-freedom rates (Maintenance Period). Patients were stratified by age (4 to <7; 7 to <12 years) and concomitant enzyme-inducing anti-seizure drug (EIASD) use.

One hundred eighty patients were enrolled (FS, n = 149; FBTCS, n = 54; GTCS, n = 31). The Core Study was completed by 146 patients (81%); the most common primary reason for discontinuation was adverse event (AE) (n = 14 [8%]). Mean (standard deviation) daily perampanel dose was 7.0 (2.6) mg/day and median (interquartile range) duration of exposure was 22.9 (2.0) weeks. The overall incidence of treatment-emergent AEs (TEAEs; 89%) was similar between patients with FS (with/without FBTCS) and GTCS. The most common TEAEs were somnolence (26%) and nasopharyngitis (19%). There were no clinically important changes observed for cognitive function, laboratory, or electrocardiogram (ECG) parameters or vital signs. Median percent reductions in seizure frequency per 28 days from Baseline were as follows: 40% (FS), 59% (FBTCS), and 69% (GTCS). Corresponding 50% responder and seizure-freedom rates were as follows: FS, 47% and 12%; FBTCS, 65% and 19%; and GTCS, 64% and 55%, respectively. Improvements in response/seizure frequency from Baseline were seen regardless of age or concomitant EIASD use.

Results from the 311 Core Study suggest that daily oral doses of adjunctive perampanel are generally safe, well tolerated, and efficacious in children age 4 to <12 years with FS (with/without FBTCS) or GTCS.

Visual snow revisited

Puledda F, Schankin C, Goadsby PJ. Visual snow syndrome: A clinical and phenotypical description of 1,100 cases. Neurology. 2020 Feb 11;94(6):e564-e574. doi: 10.1212/WNL.0000000000008909.


To validate the current criteria of visual snow and to describe its common phenotype using a substantial clinical database.

We performed a web-based survey of patients with self-assessed visual snow (n = 1,104), with either the complete visual snow syndrome (n = 1,061) or visual snow without the syndrome (n = 43). We also describe a population of patients (n = 70) with possible hallucinogen persisting perception disorder who presented clinically with visual snow syndrome.

The visual snow population had an average age of 29 years and had no sex prevalence. The disorder usually started in early life, and ≈40% of patients had symptoms for as long as they could remember. The most commonly experienced static was black and white. Floaters, afterimages, and photophobia were the most reported additional visual symptoms. A latent class analysis showed that visual snow does not present with specific clinical endophenotypes. Severity can be classified by the amount of visual symptoms experienced. Migraine and tinnitus had a very high prevalence and were independently associated with a more severe presentation of the syndrome.

Clinical characteristics of visual snow did not differ from the previous cohort in the literature, supporting validity of the current criteria. Visual snow likely represents a clinical continuum, with different degrees of severity. On the severe end of the spectrum, it is more likely to present with its common comorbid conditions, migraine and tinnitus. Visual snow does not depend on the effect of psychotropic substances on the brain.

Costello FE, Bisdorff AR, Robbins MS. Visual snow: Are we beginning to see the light? Neurology. 2020 Feb 11;94(6):241-242. doi: 10.1212/WNL.0000000000008913. (no abstract)

Kondziella D, Olsen MH, Dreier JP. Prevalence of visual snow syndrome in the UK. Eur J Neurol. 2020 Jan 30. doi: 10.1111/ene.14150. [Epub ahead of print] 


Visual snow syndrome is a recently described condition of unknown prevalence. We investigated the prevalence in a representative population sample from the UK and tested the hypothesis that visual snow syndrome is associated with young age, headache, tinnitus and mood impairment.

Using a crowdsourcing platform, we recruited a representative sample of 1015 adult laypeople from the UK, matched for age, gender and ethnicity according to national census data. Participants were unprimed, i.e. were inquired about the "frequency of certain medical conditions" but not "visual snow syndrome".

Thirty-eight of 1015 participants reported symptoms compatible with visual snow (3.7%, 95% CI 2.7-5.2), and 22/1015 met criteria for visual snow syndrome (2.2%, 95% CI 1.4-3.3). Female-to-male ratio for visual snow syndrome was 1.6:1. Subjects with visual snow syndrome were older (50.6 ±14 years) than the population mean (44.8 ±15 years), albeit not statistically different (p=0.06). Of 22 participants with visual snow syndrome, 16 had mood symptoms (72.7%; p=0.01), 13 had headache (54.5%, p=0.06), including 5 with visual migraine aura (22.7%, p=0.15), and 13 had tinnitus (59.1%, p<0.001). No participant had diabetes or a cleft lip (control questions). Following a multivariable regression analysis to adjust for age and gender, only the association between visual snow syndrome and tinnitus remained significant (OR 3.93, 95% CI 1.63-9.9; p=0.003).

The UK prevalence of visual snow syndrome is around 2%. We confirmed an association with tinnitus, but unprimed laypeople with visual snow syndrome are on average older than those seeking medical attention.

Friday, February 14, 2020

Comparative study of posterior and anterior circulation stroke in childhood

Goeggel Simonetti B, Rafay MF, Chung M, Lo WD, Beslow LA, Billinghurst LL, Fox CK, Pagnamenta A, Steinlin M, Mackay MT; IPSS Study Group. Comparative study of posterior and anterior circulation stroke in childhood: Results from the International Pediatric Stroke Study. Neurology. 2020 Jan 28;94(4):e337-e344. doi: 10.1212/WNL.0000000000008837. Epub 2019 Dec 19.


To compare risk factors, clinical presentation, and outcomes after posterior circulation arterial ischemic stroke (PCAIS) and anterior circulation arterial ischemic stroke (ACAIS) in neonates and children.

In this international multicenter observational study including neonates and children up to 18 years of age with arterial ischemic stroke (AIS), we compared clinical and radiologic features according to stroke location.

Of 2,768 AIS cases, 507 (18%) were located in the posterior circulation, 1,931 (70%) in the anterior circulation, and 330 (12%) involved both. PCAIS was less frequent in neonates compared to children (8.8% vs 22%, p < 0.001). Children with PCAIS were older than children with ACAIS (median age 7.8 [interquartile range (IQR) 3.1-14] vs 5.1 [IQR 1.5-12] years, p < 0.001), and more often presented with headache (54% vs 32%, p < 0.001) and a lower Pediatric NIH Stroke Scale score (4 [IQR 2-8] vs 8 [IQR 3-13], p = 0.001). Cervicocephalic artery dissections (CCAD) were more frequent (20% vs 8.5%, p < 0.001), while cardioembolic strokes were less frequent (19% vs 32%, p < 0.001) in PCAIS. Case fatality rates were equal in both groups (2.9%). PCAIS survivors had a better outcome (normal neurologic examination at hospital discharge in 29% vs 21%, p = 0.002) than ACAIS survivors, although this trend was only observed in children and not in neonates.

PCAIS is less common than ACAIS in both neonates and children. Children with PCAIS are older and have a higher rate of CCAD, lower clinical stroke severity, and better outcome than children with ACAIS.

Thursday, February 13, 2020

PIGP mutations

Vetro A, Pisano T, Chiaro S, Procopio E, Guerra A, Parrini E, Mei D, Virdò S, Mangone G, Azzari C, Guerrini R. Early infantile epileptic-dyskinetic encephalopathy due to biallelic PIGP mutations. Neurol Genet. 2020 Jan 2;6(1):e387.


To describe clinical, biochemical, and molecular genetic findings in a large inbred family in which 4 children with a severe early-onset epileptic-dyskinetic encephalopathy, with suppression burst EEG, harbored homozygous mutations of phosphatidylinositol glycan anchor biosynthesis, class P (PIGP), a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family.

We studied clinical features, EEG, brain MRI scans, whole-exome sequencing (WES), and measured the expression of a subset of GPI-anchored proteins (GPI-APs) in circulating granulocytes using flow cytometry.

The 4 affected children exhibited a severe neurodevelopmental disorder featuring severe hypotonia with early dyskinesia progressing to quadriplegia, associated with infantile spasms, focal, tonic, and tonic-clonic seizures and a burst suppression EEG pattern. Two of the children died prematurely between age 2 and 12 years; the remaining 2 children are aged 2 years 7 months and 7 years 4 months. The homozygous c.384del variant of PIGP, present in the 4 patients, introduces a frame shift 6 codons before the expected stop signal and is predicted to result in the synthesis of a protein longer than the wild type, with impaired functionality. We demonstrated a reduced expression of the GPI-AP CD16 in the granulocytic membrane in affected individuals.

PIGP mutations are consistently associated with an epileptic-dyskinetic encephalopathy with the features of early infantile epileptic encephalopathy with profound disability and premature death. CD16 is a valuable marker to support a genetic diagnosis of inherited GPI deficiencies.

Krenn M, Knaus A, Westphal DS, Wortmann SB, Polster T, Woermann FG, Karenfort M, Mayatepek E, Meitinger T, Wagner M, Distelmaier F. Biallelic mutations in PIGP cause developmental and epileptic encephalopathy. Ann Clin Transl Neurol. 2019 Apr 11;6(5):968-973.


Developmental and epileptic encephalopathies are characterized by infantile seizures and psychomotor delay. Glycosylphosphatidylinositol biosynthesis defects, resulting in impaired tethering of various proteins to the cell surface, represent the underlying pathology in some patients. One of the genes involved, PIGP, has recently been associated with infantile seizures and developmental delay in two siblings. Here, we report the second family with a markedly overlapping phenotype due to a homozygous frameshift mutation (c.456delA;p.Glu153Asnfs*34) in PIGP. Flow cytometry of patient granulocytes confirmed reduced expression of glycosylphosphatidylinositol-anchored proteins as functional consequence. Our findings corroborate PIGP as a monogenic disease gene for developmental and epileptic encephalopathy.

Johnstone DL, Nguyen TT, Murakami Y, Kernohan KD, Tétreault M, Goldsmith C, Doja A, Wagner JD, Huang L, Hartley T, St-Denis A, le Deist F, Majewski J, Bulman DE; Care4Rare Canada Consortium, Kinoshita T, Dyment DA, Boycott KM, Campeau PM. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum Mol Genet. 2017 May 1;26(9):1706-1715.


There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T > C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.

Myelin oligodendrocyte glycoprotein antibodies in pediatric demyelinating and encephalitic syndromes

Thaís Armangue,  Gemma Olivé-Cirera, Eugenia Martínez-Hernandez, Maria Sepulveda, Raquel Ruiz-Garcia, Marta Muñoz-Batista, et al.  Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study. Lancet Neurology.  Online Fbruary 20, 2020.


Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis.

In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity.

Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7–10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22–67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05–0·59).

The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications.

Myelin oligodendrocyte glycoprotein (MOG) antibodies were associated with a wider spectrum of pediatric autoimmune conditions than previously thought, an observational study in Spain showed.

Of 535 children with central nervous system (CNS) demyelinating disorders or encephalitis, 116 tested positive for MOG antibodies, according to Thais Armangue, MD, of Sant Joan de Deu Children's Hospital, Josep Dalmau, MD, of the University of Barcelona and University of Pennsylvania in Philadelphia, and colleagues. 

About 85% of those 116 children responded to treatment with complete or near-complete recovery, but 15% experienced severe deficits and one patient died, they reported in Lancet Neurology.

Most studies about MOG-antibody associated syndromes have focused on acquired demyelinating diseases, Dalmau said. "There have been only a few case reports, mainly including adult patients, suggesting that these antibodies can also occur in patients with encephalitis without overt clinical or MRI findings suggesting demyelinating features," he noted.

"Our study took a novel approach of prospectively examining two large cohorts of pediatric patients, one including 239 patients with demyelinating syndromes and the other 296 patients with all types of consecutively identified encephalitis in 40 Spanish centers," he told MedPage Today.

Of the 116 children diagnosed with MOG antibodies, 94 (39%) were in the group of demyelinating syndromes and 22 (7%) were in the encephalitis group. In the first group, the researchers confirmed the association of MOG antibodies with demyelinating syndromes previously known, including acute disseminated encephalomyelitis (ADEM), optic neuritis, and myelitis.

"The major surprise came from the group of patients with encephalitis, who had syndromes in which the presence of MOG antibodies is rarely considered or even suspected," Dalmau said. "This is important because nowadays about 40% of patients with encephalitis remain without a clear etiology."

MOG antibodies damage the myelin sheath surrounding nerve fibers, causing symptoms like vision loss, muscle weakness, and pain. Many children may only experience one MOG antibody disease event, but some may relapse months or years later. The full range of diseases associated with MOG antibodies is unknown.

In this study, researchers followed children with a median age of 6 in Spanish hospitals from 2013 to 2018. Children who tested positive for MOG antibodies were assessed over a median of 42 months.

Of the 116 children who tested positive for MOG antibodies, 24% had syndromes not previously associated with MOG antibodies.

During follow-up, 33 children had relapses, including 15 children who had more than one relapse. The likelihood of relapse was similar regardless of syndrome at disease onset. Time to antibody negativity was longer in patients with relapses (HR 0.18, 95% CI 0.05-0.59).

Steroids, intravenous immunoglobulin, or plasma exchange were used in 86% of children at diagnosis and 97% of children at relapse. Rituximab (Rituxan) was used in 11 children at relapse.

Most of the 116 patients who were MOG-positive had substantial recovery (85% had a score of 0 or 1 on the modified Rankin scale, indicating no significant disability). One boy died at 4 days follow-up, and the remaining children had moderate to severe deficits. Patterns associated with poor prognosis included ADEM-like relapses with changes that resembled leukodystrophy, and extensive cortical encephalitis evolving to brain atrophy.

At last follow-up, only five patients (4%) had been diagnosed with multiple sclerosis (MS), supporting the idea that MOG antibody-associated syndromes and MS are different pathological entities, the authors noted.

This research is "a milestone in the understanding of MOG antibody-associated syndromes," wrote Romain Marignier, MD, PhD, of the Hospices Civils de Lyon in France, in an accompanying comment.

"In view of the very broad clinical spectrum now associated with MOG autoimmunity, the next challenge will be to identify the optimal therapeutic strategy for each clinical presentation," he added. "This objective is closely connected to a better understanding of the pathogenic role of MOG antibodies, and the need for early, robust, and specific prognostic factors of relapse and disability." 

This study has several limitations, the researchers noted. It was not registry-based and could not assess the incidence and prevalence of MOG antibody-associated syndromes. Because follow-up was short, the frequency of relapses or MS development may have been underestimated. The study also did not include cognitive evaluations.

Some of the cases in the study "would have been missed if it were not for the systematic screening of our study," the researchers pointed out. "Overall, our findings are important because 85% of patients in this study had substantial recovery, illustrating the need for an update of the existing classification and terminology of MOG antibody-associated syndromes."


Submandibular gland botulinum neurotoxin A injection for drooling

Van Hulst K, Van Der Burg JJ, Jongerius PH, Geurts AC, Erasmus CE. Changes in severity and impact of drooling after submandibular gland botulinum neurotoxin A injections in children with neurodevelopmental disabilities. Dev Med Child Neurol. 2020 Mar;62(3):354-362.


To examine changes in objective and subjective drooling severity measures after submandibular botulinum neurotoxin A injection in children with neurodevelopmental disabilities, explore their relationship, and evaluate if clinically relevant responses relate to changes in the impact of drooling.

This longitudinal, observational cohort study involved 160 children (92 males, 68 females; 3-17y, mean 9y 1mo, SD 3y 6mo) treated between 2000 and 2012 at the Radboud University Medical Center, Nijmegen, the Netherlands. Repeated measures analysis of variance was used to compare the 5-minute Drooling Quotient (DQ5) and Visual Analogue Scale (VAS) for drooling severity pretreatment and posttreatment, and Pearson's rho to assess their association. A parent questionnaire was used to assess drooling impact in responders (defined as ≥50% reduction in DQ5 and/or ≥2 SD reduction in VAS for drooling severity 8wks postintervention) and non-responders.

One hundred and twelve children (70%) were responders. Their mean VAS for drooling severity and DQ5 scores were significantly lower 32 weeks postintervention compared to baseline. At baseline, the VAS for drooling severity-DQ5 relationship was 'weak' (rs =0.15, p=0.060), whereas it was 'fair' at 8 weeks (rs =0.43, p=0.000) and 32 weeks (rs =0.30, p=0.000). For responders, a significant change was found regarding the impact of drooling on daily care and social interactions at 8 weeks after intervention; most of these effects were maintained at 32 weeks.

A clinically relevant response based on a combination of objective and subjective measures of drooling severity was accompanied by positive changes regarding the impact of drooling on daily care and social interactions.

Botulinum neurotoxin A injection into the submandibular glands reduced drooling severity in 70% of children with neurodevelopmental disabilities. Objective (5-minute Drooling Quotient) and subjective (Visual Analogue Scale for drooling severity) measures correlated 8 and 32 weeks after treatment. Objective and subjective measures complemented each other when changes in drooling severity were assessed. Reduced drooling severity was accompanied by positive changes with regard to the impact of drooling.

Courtesy of:

Wednesday, February 12, 2020

Pelletier malpractice lawsuit 7

Boston Children’s Hospital’s own in-house ethicist questioned the hospital’s handling of the high-profile dispute over the care of Justina Pelletier that broke out between her parents and her doctors, according to documents in the lawsuit that is underway in Suffolk Superior Court.

Pelletier’s doctors soon cut her parents out of the decision making, and the couple’s daughter ultimately ended up in the hospital’s locked psychiatric unit for nine months, with the state’s child protection agency assuming custody.

Christine Mitchell, longtime director of Children’s Hospital’s Office of Ethics, e-mailed other hospital employees reviewing 14-year-old Justina’s care in 2013 to say she felt that her medical team should improve communications with her parents, Linda and Louis Pelletier.

Mitchell said she worried the team’s decision to shut the parents out of meetings and decisions about care was counterproductive.

“I am concerned that getting people together . . . who all share the experience of difficult conversations with these parents (including us) can lead to a tendency to see the parents as the problem and over-determine a solution that works against re-uniting Justina and her parents,” Mitchell wrote.

Mitchell’s May 7, 2013, e-mail was sent roughly three months after the Pelletiers rushed their daughter to Children’s for care — and about a month into her stay in the hospital’s locked psychiatric wing.

The e-mail was one of several hospital communications the Pelletiers’ lawyers shared with jurors Thursday in a case that pits parental rights against doctors’ authority to direct treatment.

The Pelletiers accuse Children’s and four of its providers of violating the family’s civil rights by telling them the state would take the teenager away if her parents didn’t consent to the doctors’ treatment plan and, after she was removed from their custody, limiting their ability to see her.

They also allege negligence by the four providers for treatment decisions that they say ignored the regimen set by her doctors at Tufts Medical Center. Tufts was treating Justina Pelletier for mitochondrial disease, a group of rare genetic disorders that affect how cells produce energy.

Days after the Pelletiers raced to Children’s in February 2013, on the advice of Justina Pelletier’s lead doctor at Tufts, the Children’s specialists determined that Pelletier’s health problems — difficulty walking, eating, and slurring speech — were largely psychiatric. They recommended stopping the mitochondrial medications prescribed by her Tufts doctor and said she needed inpatient psychiatric care instead.

Pelletier’s parents sharply disagreed with the Children’s team’s diagnosis and treatment plan; they believed she was suffering from mitochondrial disease, not from a mental health issue. So the Children’s providers contacted the state Department of Children and Families, saying they suspected her parents were overmedicalizing her, placing her in jeopardy. That’s when DCF stepped in and a Juvenile Court judge awarded the state custody.

But e-mails shown to jurors on Thursday indicated that some of the Children’s specialists who were treating Pelletier thought her problems might be connected to mitochondrial disease. Others thought both mito and psychiatric problems were fueling her ailments.

“It sounded clear to me from our meeting with all the involved clinicians [on May 3, 2013] that the mitochondrial disease . . . diagnosis stands,” Mitchell wrote in her e-mail to her Children’s colleagues.

“I’m leaning toward stressing the med-psych dual diagnosis situation this patient has and clarifying for parents how to participate in helping their daughter.” 

Another string of e-mails from early May 2013 shared with jurors indicate the hospital’s chief psychiatrist, Dr. David DeMaso, was upset that Mitchell had called for an ethics consultation with Pelletier’s psychiatric care team. Although Pelletier had already spent a month in the Children’s psychiatric unit, DeMaso said the psychiatric team had not yet met with other hospital providers to map out a care plan.

“I thought your calling together such a meeting was premature,” DeMaso said. The psychiatric staff “needed to sit down (and should have already sat down) with the other medical providers . . . prior to any ethics (or other) consultation to discuss this youngster and develop an approach and management plan.”

“I did not see this as the job of the Ethics Committee,” DeMaso wrote.

Lawyers for Children’s and one of the doctors the Pelletiers are suing did not address the e-mails during testimony on Thursday. The lawyers instead questioned the qualifications of a bioethicist called by the Pelletiers’ lawyer to offer expert testimony about the e-mails and Justina Pelletier’s care.

The ethicist, Diane O’Leary, a visiting fellow at the Rotman Institute of Philosophy in Canada, said the Children’s records she reviewed did not accurately reflect that some providers at Children’s thought mitochondrial disease was at least partially linked to Pelletier’s problems.

“That disparity had a very big impact” on the Pelletiers’ involvement in their daughter’s care, O’Leary said.

But Children’s lawyers noted that O’Leary had no medical training and was not qualified, they said, to comment on standards of care.

Pelletier malpractice lawsuit 6

The Suffolk Superior Court judge overseeing the medical malpractice trial brought against Boston Children’s Hospital by a chronically ill teen patient and her parents made it clear Thursday that he thought the civil case was thin, lacked evidence, and was short on relevant experts.

“You have to show more than just generalized evidence,” Associate Justice Anthony M. Campo told the Pelletiers’ team of four lawyers. “It’s not sufficient to say, ‘It’s in the medical records, figure it out.' ”

Campo’s remarks came after the family’s lawyers rested their case after nearly three weeks of testimony. The jury was not in the courtroom.

Justina Pelletier’s parents sued the renowned pediatric hospital and four caregivers they battled with over their daughter’s diagnosis and treatment in 2013.

The state Department of Children and Families took custody of their 14-year-old daughter and she remained in the psychiatric unit at the hospital for 10 months.

The lawsuit accuses a neurologist, psychologist, psychiatrist, and former pediatrician at the hospital of negligence.

“What has the jury heard about how they worked together?” Campo wanted to know. “You have to prove the case, every element of your case ...

“What I’m hearing from the plaintiffs is ‘they and them,'" he said. "It’s just grouping them all together.”

The entire medical team had worked together to prevent Justina Pelletier’s reunification with her parents, the Pelletiers’ lead attorney Kathy Jo Cook argued.

After a brief recess, Campo returned to the bench and tossed one of the lawsuit’s claims — an alleged violation of the Pelletiers’ civil rights by pediatrician Alice Newton.

Newton previously ran the hospital’s child protection unit for seven years. While there, she gained a reputation as a controversial and outspoken child abuse specialist.

Newton’s attorney said his client’s only involvement with the case was attending two meetings, not as part of the medical team but as part of the child protection team, in the first few days of Justina Pelletier’s arrival at the hospital’s emergency room.

“She never saw, spoke [with], or examined Justina Pelletier," Newton’s lawyer, John Cassidy, said. “She never saw or spoke with either parent.”

When the jury returned to the courtroom, lawyers for Boston Children’s Hospital called their first witness: Jurriaan Peters, a neurologist.

Peters, 45, testified that the extent of his care for Justina Pelletier was limited to five days, from her Feb. 10, 2011, arrival until Feb. 15, 2011.

He was instantly concerned, Peters testified.

“A 14-year-old who doesn’t walk, is incontinent for urine, who is lethargic and is unable to eat, drink, or swallow, can’t lift her arms and doesn’t make eye contact, that is very concerning," he said.

Within her first 24 hours at the hospital, Peters had either spoken with, or reached out to, the majority of Justina Pelletier’s former doctors, he said.

From each, Peters said, “I heard the same stories.”

“The same theme emerged with every phone call," he said.

The parents were difficult, their daughter’s behavior regressed when she was around her family, and there was no medical explanation for her problems, he said. Many held a high suspicion that there was a psychological or psychiatric component to her condition, Peters testified.

A former neurologist told him that Justina Pelletier’s treatment was “complicated by very nice, intelligent, well-intending parents," medical records showed.

As a result, that neurologist concluded, Justina Pelletier may have “developed a pathological feedback loop” where her symptoms, when expressed, were validated by her parents.

Peters translated that into laymen’s terms: “Anytime a person says they’re sick, then it’s endorsed or validated.”

He questioned the mitochondrial disease diagnosis that Linda Pelletier insisted her daughter had, “but I didn’t discard it," Peters said.

His medical notes also reflected his "concern with mom’s black and white thinking.”

Her daughter’s doctors, in Linda Pelletier’s opinion, had been either incompetent or unsatisfactory, or exceptional and unique, Peters told the jury.

“There was little room for gray or maybe,” he said. “It was either/or. It was either really good or really bad.”

Justina Pelletier’s medical history, Peters said, was filled with classic red flags for “over-medicalization” at the hands of her parents.

She had a “patchy network of providers,” she took numerous medications — some prescribed to combat side effects of other drugs — and “I saw a big, big, big number of tests,” he said.

“When there’s no single person ... who is coordinating all this care, it gets risky,” Peters said.

Tuesday, February 11, 2020

Pelletier malpractice lawsuit 5

Justina Pelletier’s former pediatrician never thought his patient was in danger of medical abuse by her parents, according to testimony Friday in Suffolk Superior Court in the Pelletiers’ lawsuit against Boston Children’s Hospital and four providers who treated her in 2013.

Dr. Thomas Binder, Pelletier’s Connecticut pediatrician until 2012, did not appear in court, but lawyers read from a deposition he provided.

In that deposition, Binder said Pelletier experienced an increasing number of medical problems around 2010, when she was about 12 years old. He said he experienced difficulty in dealing with her often demanding parents.

Binder said a school nurse called him in May 2011 because Pelletier was often absent from school for medical reasons.

The school nurse asked him whether Connecticut’s child protective agency had been involved. But Binder, who as a pediatrician would be required to alert authorities if he suspected child abuse, said in his deposition he didn’t see a need to do that.

“I never had a situation where I felt she was in danger of serious abuse or neglect,” he told attorneys in the case, according to his deposition…

The next month, according to Binder’s deposition, as Connecticut’s child protective agency was investigating the Pelletiers, a child psychiatrist treating the girl called Binder and told him she thought the girl suffered from a somatoform disorder — a psychiatric illness that causes physical symptoms. The psychiatrist said she needed intensive inpatient psychiatric treatment, according to Binder’s deposition.

“I agreed her plan was a reasonable plan,” he said.

A couple of weeks later, in January 2012, Dr. Alejandro Flores, a gastroenterologist who had been treating Pelletier at Tufts Medical Center Floating Hospital for Children, also told Binder he suspected she suffered from a somatoform disorder, according to the deposition.

Flores is the specialist the Pelletiers planned to see when they rushed their daughter to Children’s Hospital in February 2013, at the suggestion of her Tufts doctors, because she was having trouble eating, walking, and talking.

But in a later e-mail, Flores told Pelletier’s lead doctor at Tufts, Dr. Mark Korson, that he was unable to see her because of “legal restrictions.”

It’s unclear what Flores meant, and lawyers for the Pelletiers and Children’s hospital clashed in court Friday over whether the jury should be allowed to see that e-mail.

The Pelletiers claim Children’s doctors who treated their daughter in 2013 shut Flores and Korson out of her care, but Children’s denies that.

Suffolk Superior Court Associate Justice Anthony M. Campo said he would consider allowing Flores’ e-mail to be shown to the jury if Flores testifies. 

Monday, February 10, 2020

Pelletier malpractice lawsuit 4

Like every day for the past week, Justina Pelletier’s family rolled her into court Monday morning in a wheelchair. Her nails had a fresh coat of lavender polish, and a fuzzy gray blanket lay over her legs.

Now 21 years old, Pelletier  took the stand in the malpractice suit she and her family are bringing against Boston Children’s Hospital and the doctors who treated her there.
As she described the nine months she was in the hospital’s locked psychiatric ward, Pelletier began to sob. Watching her from the courtroom’s front row and waiting for her own turn at the stand was Dr. Colleen Ryan, the psychiatrist who was in charge of Pelletier’s care during that time.

Pelletier first arrived at Boston Children’s Hospital at 4 a.m. on Feb. 10, 2013, with severe stomach pain and dehydration. On a scale of one to 10, Pelletier said the pain was at a seven. Four days later, she said, she was making Valentine’s Day cookies with her mother when several guards in black uniforms swept her away. 

“All of a sudden, I just didn’t see her. She wasn’t there,” Pelletier said.

“Did you get a chance to say goodbye?” John Martin, Pelletier’s lawyer, asked her.

“No,” she said.

The doctors on Pelletier’s care team believed her symptoms were largely psychological, rather than due to a rare genetic condition called mitochondrial disease, as her parents believed. The illness affects how cells create energy. Instead, the doctors suspected Pelletier’s parents of abuse that might be causing some of her symptoms. So later that day, they moved her to the hospital’s locked psychiatric ward.

“All of a sudden, they said, 'You are going to go up there,' and I didn’t know why,” Pelletier said at the trial. “I didn’t want to. I just kept saying I wanted to go home.”

Once Pelletier was in the psychiatric ward, she said the doctors began limiting her contact with her family to an hour of visitation and 20 minutes of phone calls per week. She said her mother wasn’t allowed to ask her about her treatment or even how she was doing.

“I was able to talk to them for a little bit but someone was listening. If [my parents] said something about how I was feeling, they would stop it. Hang up,” Pelletier said, her voice wavering. “It was really hard to be away from my family.”

Pelletier said the medical staff was cruel to her at times during her stay in the psychiatric ward. She told her lawyer they would leave her on the toilet when she couldn’t defecate or in her wheelchair for intolerable periods of time.

“They didn’t believe [my pain], and they hurt me so much,” Pelletier said. “I kept getting weaker.”

Boston Children's Hospital doctor Colleen Ryan insisted she and other medical staff were doing what was best for Pelletier. She testified that Pelletier’s parents would obsess over her medical problems in a way that would make her worse. Ryan told jurors that’s why she recommended that the hospital and Department of Children and Families, which had taken custody of Pelletier, limit the contact between the girl and her parents.

“We had Justina’s best interests in mind, and we knew if there was less focus on negative aspects of her health and more on her positive experiences, then that would be beneficial to her health,” Ryan said.

“Don’t you think it’s reasonable for a mother to ask her daughter, 'Hey, how are you feeling? Has someone taken care of that dandruff yet?' ” Martin asked Ryan during the trial.

“Of course, as a mother, I understand that,” Ryan replied. “But to point out and insist on those things – we did not think that was good for her.”

In earlier statements, one of Ryan’s lawyers said that Boston Children’s Hospital doctors had learned that Pelletier seemed to do better when her parents were not present. In her testimony, Ryan said the parents often became belligerent during meetings, which added to suspicions that her parents might have actually been causing some of Pelletier’s symptoms.

“We were having a family meeting with [Department of Children and Families] and the parents – there was some very inappropriate and improper conduct going on,” she said. “It was very concerning.”

Ryan said she and her team tried repeatedly to engage the parents in Pelletier’s treatment, but she claims they were simply too combative.

“We always tried to involve the family,” she said. “We never got past the contentiousness. We tried so many times.”

Pelletier is now back with her parents and receiving treatment for mitochondrial disease from a doctor in Connecticut. She described how she’s improved in recent years through art therapy and physical activity. Her lawyer showed the jury drawings that Pelletier created in recent years – realistic animals drawn in color and black and white.

And in a recent video introduced by the defense, Pelletier is riding a horse named Sandman – one of her favorites – during a competition. She kicks the horse into a trot and then eases him back into a walk.

“You’ve gotten very good,” Cohen said, pointing to a photo with blue ribbons for riding competitions stuck to Pelletier’s chest.

“Thank you,” she said.

Pelletier malpractice lawsuit 3

Louis Pelletier’s voice began to break as he read letters from his daughter, Justina, to a jury from the witness stand on Friday. She sent them to him from the locked psychiatric ward in Boston Children’s Hospital.

“Dear Daddy. Happy Daddy’s day,” he read. He paused. His voice scraped over the words, “I love you so much. You’re the best daddy I could ever have. Always. Justina.”

Justina Pelletier, 21, was 14 when she wrote those words. She’s now at the center of a protracted lawsuit that her family is bringing against Boston Children’s and the doctors who treated her there. The family alleges the hospital kidnapped their daughter and mistreated Justina while she was there. The doctors say they provided Justina with appropriate care and took necessary actions to protect her from what they believed was child abuse at home.

During his testimony, Pelletier recounted the first few days Justina was in Boston Children’s Hospital. She was admitted on Feb. 10, 2013, at 4 in the morning for severe abdominal pain, a problem that she said had plagued her for her entire life. A few days later, Pelletier and his wife were on the phone with Boston Children’s doctors, asking them to involve Justina’s previous doctors from Tufts Medical Center in her care.

But doctors at Boston Children’s Hospital had begun to come to the conclusion that Justina’s medical problems were largely due to psychiatric issues. They wanted to put Justina in intensive psychiatric care in the hospital. Pelletier said that was fine, as long as Justina’s former doctors at Tufts Medical Center agreed with the plan, but as far as he knew, Boston Children’s Hospital wasn’t doing that.

He and his wife both got “extremely upset,” according to a note written by hospital staff on Feb. 13, 2013, that was read aloud by John Martin, one of Pelletier’s lawyers.

“ '[Parents] felt treatment goals did not meet those of previous providers,' ” Martin continued to read from the note during Louis Pelletier's testimony. “ 'Parents stated they did not believe in the psychological bologna.' Did you say that?”

“I probably did,” Pelletier said. “We just went through a whole process where [doctors] said Justina’s pain was in her head. We found out [later] the pain was really there in her stomach.”

Over the next day, Pelletier said he decided to take Justina out of Boston Children’s and take her back to Tufts Medical.

“It was Valentine’s Day,” he recalled. He arrived at the hospital for the first time and went straight to the nurse’s station to sign his daughter out. “I went to the desk multiple times for an hour. They said we’re trying to reach the attending, but there was no response.”

Pelletier said he started to feel like he and his wife would never get Justina out of the hospital. He called the Boston police, saying that Boston Children’s had kidnapped their daughter. Then, he said security guards showed up and removed the parents from the hospital premises.

“Numerous Boston Children’s security. They had uniforms on. They gave us a no trespass and said we weren’t allowed on the premises and we had to go to a [Department of Children and Families] office in Roxbury,” Pelletier testified.

During the cross-examination, the defense attorney, Ellen Cohen, read a report from a DCF employee that said Boston police officers had actually escorted the Pelletiers from the hospital, not hospital security.

“Parents were escorted by Boston police. They said parents became belligerent and out of control,” Cohen read. “According to reporter, mother and father were disrespectful to staff, calling names and being rude. They were the ones who called Boston police, saying the hospital was holding their daughter against their permission.”

Pelletier denied calling the staff names or being rude that day, though he said he remembers threatening the staff at Boston Children’s with legal action. He said he learned that Boston Children’s doctors had filed a 51A — a child abuse report — against him and his wife. They had been suspected of factitious disorder by proxy, a type of medical abuse where parents are doing something to cause the child’s symptoms or making them up. When Pelletier learned this, he said he felt betrayed.

“It was just a punch in the stomach,” he said. “We were falsely accused of doing something that we had not done. Now we were fighting for our daughter’s life.”

That report eventually led to the state taking custody of Justina, and the family was only allowed to visit her for an hour a week and speak to her on the phone for 20 minutes a week. According to their claims, doctors believed that, due to the nature of the alleged abuse, this was the best way for the girl to heal.

All of Justina’s communication and contact with her family was monitored, including the letters she sent her parents. In some, she would fold up slips of paper and tape them so they would be hidden from the hospital staff reviewing them.

“They pushed me to do stuff that is hard. They yell at me until I do it,” Pelletier read from one such slip. “They say stuff is in my head. Or she pushes me too hard to do stuff I can’t do [like walk] and blames it on family.”

Justina sat in the courtroom as her father read the letters. Her brows furrowed, and she closed her eyes.

The jury will decide if the doctors took the right course of action or, as the parents say, they violated the family’s civil rights.