The head of the non-profit group coordinating organ donation for most of New Jersey hopes the story of Mikey Lavecchia doesn't taint the public's view of organ donation.
"I hope the public understands that this is not an issue that was created by the need to have an organ donation," Joe Roth, president and CEO of NJ Sharing Network, said.
Michael "Mikey" Lavecchia, 13, was pronounced dead Sunday by doctors at St. Joseph's Medical Center in Paterson. He was in a car that crashed into a truck Saturday on the side of Route 80 eastbound in Wayne, killing the other two occupants, including his father, Michael Jr.
Laureen Lavecchia chose to donate Mikey's organs. As she kept a vigil over him Sunday night while waiting for a recipient, she saw him move his legs, shoulders and arms.
A review of scientific literature on movements after brain death, published in March 2009 in the Canadian Journal of Neurological Sciences, found movements were present in as many as half of heart-beating cadavers, though it's not clear why. The authors concluded such movements "do not invalidate" a brain death diagnosis.
Laureen has since moved Mikey, who recently moved with his father from Brentwood, N.Y., to East Stroudsburg, Pa., to Robert Wood Johnson University Hospital in New Brunswick. She said Thursday there had been no change in Mikey's condition...
"The staff at our children's hospital is vastly experienced in providing clinical care in this area and remains committed to providing any assistance to the Lavecchia family in seeking answers to any unanswered questions. Our desire is to be supportive of the family as they continue to deal with this tragedy."
Laureen has said she has not ruled out donating Mikey's organs, but is focused on his recovery.
Roth, who said NJ Sharing Network has helped coordinate more than 400 transplants, said the Lavecchias' situation is a first.
"We've not had situations like this in my experience," he said.
NJ Sharing Network doesn't become involved with patients until they're pronounced dead, Roth said. Families sometimes back out after that point, but usually because not every family member agrees with the decision to donate.
The need for organ transplants is huge, Roth said.
"Right now, just New Jersey patients, there are over 5,000 people waiting for transplants," he said...
"My heart goes out to her," Kuzminksi said of Laureen Lavecchia. "I pray there is a better outcome than what it looks like there's going to be. I hope that her decision to donate his organs will still be the same decision. To have something come positive come out of a tragedy was a very healing experience for our family."
http://www.nj.com/passaic-county/index.ssf/2015/08/could_boy_declared_brain_dead_scare_off_organ_dono.html
Friday, August 21, 2015
Thursday, August 20, 2015
Next-generation sequencing still needs our generation's clinicians
In this issue of Neurology Genetics, Tian et al report on a robust and comprehensive NGS-based panel testing for 236 neuromuscular-related genes. They report that this targeted capture approach resulted in an excellent yield, identifying deleterious mutations in 29 of 35 families (83%) studied in their cohort of patients with clinically heterogeneous neuromuscular diseases, including congenital myopathies, limb-girdle muscular dystrophies (LGMDs), Charcot-Marie-Tooth (CMT) disease, metabolic myopathies, myotonic syndromes, and ion channel diseases. They considered the diagnosis to be definitive in 21 families (60%) and likely in an additional 8 families (23%). The authors correctly point out that the strength of their NGS and capture approach is the excellent coverage (with a mean depth of approximately 1,000-fold) and the considerable number of genes targeted in parallel...
It is essential to have a solid understanding of the extended phenotype (which may include histology, physiology, or imaging) before ordering genetic testing not only to ensure that the appropriate panel is ordered but especially to recognize those conditions for which NGS sequencing is unable to reliably identify the pathogenic genetic cause. In fact, this is the case for the most common genetic neuromuscular disorders, including trinucleotide repeat expansions (myotonic dystrophy, Friedreich ataxia), deletions, duplications, or, in particular, “copy number neutral” inversions of multiple exons—as NGS is now getting better at detecting larger deletions or duplications (Duchenne/Becker muscular dystrophy)—deletions situated in highly similar duplicated genomic regions (spinal muscular atrophy), contractions or duplications of genomic regions (facioscapulohumeral muscular dystrophy and CMT type 1A), abnormal methylation (Prader-Willi syndrome, an important differential diagnosis in the hypotonic infant), and chromosomal disorders (molecular karyotype by array comparative genomic hybridization may be better here). For this reason alone, deep phenotyping and a hierarchical differential diagnosis are imperative when selecting the genetic testing methodology appropriate for an individual patient.
When considering scenario 3 (potentially “missing” mutation), it is helpful to realize that in contrast to WES, NGS-based panels typically cover all genes included in the panel at superior depth. Deletion/duplication testing (to assess for copy number variations) can supplement NGS, thus decreasing the risk of “missed” mutations. Coverage for WES may be more incomplete, with only 80%–85% of the exome captured and at a lower depth...
One of the main hurdles in broad panel-based testing, especially in WES and WGS, is scenario 4, the interpretation of a large number of sequence VUS, which can be incredibly time consuming and may result in incorrectly assigned pathogenicity or missed causative variants. It is the laboratory's responsibility to help evaluate any variants found with regard to their predicted pathogenicity (based on allele frequency, in silico analysis tools, data in published reports and databases, and tools for predicting the functional effects of amino acid substitutions such as PolyPhen and SIFT, as detailed nicely in Tian et al.). Given the number of sequence variants reported by WES, it is essential for the clinician to have strategies in place for sorting through the variants reported by the genetic laboratory as potentially deleterious. This list will be narrowed by the laboratory to initially include only those with disease association; however, the likely still considerable number of variants can be more successfully analyzed with a hypothesis-driven condensed candidate gene list in mind, based on a hierarchical clinical diagnosis of a well-phenotyped patient.
It is essential to have a solid understanding of the extended phenotype (which may include histology, physiology, or imaging) before ordering genetic testing not only to ensure that the appropriate panel is ordered but especially to recognize those conditions for which NGS sequencing is unable to reliably identify the pathogenic genetic cause. In fact, this is the case for the most common genetic neuromuscular disorders, including trinucleotide repeat expansions (myotonic dystrophy, Friedreich ataxia), deletions, duplications, or, in particular, “copy number neutral” inversions of multiple exons—as NGS is now getting better at detecting larger deletions or duplications (Duchenne/Becker muscular dystrophy)—deletions situated in highly similar duplicated genomic regions (spinal muscular atrophy), contractions or duplications of genomic regions (facioscapulohumeral muscular dystrophy and CMT type 1A), abnormal methylation (Prader-Willi syndrome, an important differential diagnosis in the hypotonic infant), and chromosomal disorders (molecular karyotype by array comparative genomic hybridization may be better here). For this reason alone, deep phenotyping and a hierarchical differential diagnosis are imperative when selecting the genetic testing methodology appropriate for an individual patient.
NGS, like every form of genetic testing, not only requires such careful “pre-testing” phenotyping but also requires an equally careful “post-testing” analysis. The post-testing challenges for the clinician arise from interpreting the results reported by the genetic laboratory. Using this approach of “pre-test” deep phenotyping, NGS, and “post-test” clinical plausibility checking, the potential outcomes of NGS for the clinician include (1) genetic diagnosis confirmed, as suspected; (2) genetic diagnosis confirmed, but not as suspected; (3) incomplete genetic diagnosis in a highly suspected gene, such as a missing second pathogenic allele in a recessive disease; (4) genetic variants of unknown significance (VUS) in more than 1 gene, which are possibly causative; and (5) no genetic diagnosis achieved. For the purpose of this discussion, we will not consider the equally vexing problem of the identification of unexpected secondary findings on WES or WGS that are unrelated to the patient's underlying clinical diagnosis but may have significant implications for future medical management...
When considering scenario 3 (potentially “missing” mutation), it is helpful to realize that in contrast to WES, NGS-based panels typically cover all genes included in the panel at superior depth. Deletion/duplication testing (to assess for copy number variations) can supplement NGS, thus decreasing the risk of “missed” mutations. Coverage for WES may be more incomplete, with only 80%–85% of the exome captured and at a lower depth...
One of the main hurdles in broad panel-based testing, especially in WES and WGS, is scenario 4, the interpretation of a large number of sequence VUS, which can be incredibly time consuming and may result in incorrectly assigned pathogenicity or missed causative variants. It is the laboratory's responsibility to help evaluate any variants found with regard to their predicted pathogenicity (based on allele frequency, in silico analysis tools, data in published reports and databases, and tools for predicting the functional effects of amino acid substitutions such as PolyPhen and SIFT, as detailed nicely in Tian et al.). Given the number of sequence variants reported by WES, it is essential for the clinician to have strategies in place for sorting through the variants reported by the genetic laboratory as potentially deleterious. This list will be narrowed by the laboratory to initially include only those with disease association; however, the likely still considerable number of variants can be more successfully analyzed with a hypothesis-driven condensed candidate gene list in mind, based on a hierarchical clinical diagnosis of a well-phenotyped patient.
A. Reghan Foley, MD, Sandra Donkervoort, MS, CGC and Carsten
G. Bönnemann, MD. Next-generation sequencing still needs our generation's clinicians Neurol Genet August 2015 Published online August 13, 2015.
Author inflation
How Many Scientists Does It Take to Write a Paper? Apparently, Thousands
Scientific journals see a spike in number of contributors; 24 pages of alphabetized co-authors
A Frenchman named Georges Aad [pictured here] may have the most prominent name in particle physics.
In less than a decade, Dr. Aad, who lives in Marseilles, France, has appeared as the lead author on 458 scientific papers. Nobody knows just how many scientists it may take to screw in a light bulb, but it took 5,154 researchers to write one physics paper earlier this year—likely a record—and Dr. Aad led the list.
His scientific renown is a tribute to alphabetical order.
Almost every paper by “G. Aad et al.” involves so many researchers that they decided to always list themselves in alphabetical order. Their recent paper, published in the journal Physical Review Letters, features 24 pages of alphabetized co-authors led by Dr. Aad….
Things have accelerated. The 1993 Ig Nobel Prize for literature was awarded to Eric Topol, R. Califf, F. Van de Werf, P. W. Armstrong, and their 972 co-authors, for publishing a medical research paper which has one hundred times as many authors as pages. [The study was published in The New England Journal of Medicine [NEJM], vol. 329, no. 10, September 2, 1993, pp. 673-82. The authors are from the following countries: Australia, Belgium, Canada, France, Germany, Ireland, Israel, Luxembourg, The Netherlands, New Zealand, Poland, Spain, Switzerland, United Kingdom, United States. NEJM Executive editor Marcia Angel attended the Ig Nobel ceremony, accepting the prize on behalf of the co-authors, who could not agree on the wording of an acceptance speech.
Aad G, Abbott B, Abdallah J, et al. Combined Measurement of the Higgs Boson Mass in pp Collisions at sqrt[s]=7 and 8 TeV with the ATLAS and CMS Experiments. Phys Rev Lett. 2015 May 15;114(19):191803. Epub 2015 May 14.
http://www.improbable.com/2015/08/09/63778/
http://www.wsj.com/articles/how-many-scientists-does-it-take-to-write-a-paper-apparently-thousands-1439169200
Courtesy of: http://www.medpagetoday.com/PrimaryCare/GeneralPrimaryCare/53085
Scientific journals see a spike in number of contributors; 24 pages of alphabetized co-authors
A Frenchman named Georges Aad [pictured here] may have the most prominent name in particle physics.
In less than a decade, Dr. Aad, who lives in Marseilles, France, has appeared as the lead author on 458 scientific papers. Nobody knows just how many scientists it may take to screw in a light bulb, but it took 5,154 researchers to write one physics paper earlier this year—likely a record—and Dr. Aad led the list.
His scientific renown is a tribute to alphabetical order.
Almost every paper by “G. Aad et al.” involves so many researchers that they decided to always list themselves in alphabetical order. Their recent paper, published in the journal Physical Review Letters, features 24 pages of alphabetized co-authors led by Dr. Aad….
Things have accelerated. The 1993 Ig Nobel Prize for literature was awarded to Eric Topol, R. Califf, F. Van de Werf, P. W. Armstrong, and their 972 co-authors, for publishing a medical research paper which has one hundred times as many authors as pages. [The study was published in The New England Journal of Medicine [NEJM], vol. 329, no. 10, September 2, 1993, pp. 673-82. The authors are from the following countries: Australia, Belgium, Canada, France, Germany, Ireland, Israel, Luxembourg, The Netherlands, New Zealand, Poland, Spain, Switzerland, United Kingdom, United States. NEJM Executive editor Marcia Angel attended the Ig Nobel ceremony, accepting the prize on behalf of the co-authors, who could not agree on the wording of an acceptance speech.
Aad G, Abbott B, Abdallah J, et al. Combined Measurement of the Higgs Boson Mass in pp Collisions at sqrt[s]=7 and 8 TeV with the ATLAS and CMS Experiments. Phys Rev Lett. 2015 May 15;114(19):191803. Epub 2015 May 14.
http://www.improbable.com/2015/08/09/63778/
http://www.wsj.com/articles/how-many-scientists-does-it-take-to-write-a-paper-apparently-thousands-1439169200
Courtesy of: http://www.medpagetoday.com/PrimaryCare/GeneralPrimaryCare/53085
Sanfilippo isolation
On Tuesday, Glenn O'Neill crossed off the number 453 from a large white sheet of paper hanging in the kitchen of his Columbus, South Carolina, home.
It's the 453rd reminder of how many days he and his family have been living in self-imposed quarantine. "We are just trying to save her life," Glenn, 42, tells PEOPLE of his daughter, Eliza. "The piece of paper reminds us how far we have come and how much further we need to get it."
Eliza O'Neill, a bubbly 5-year-old, was diagnosed in July, 2013, with Sanfilippo syndrome, type A – the most severe form of the rare genetic disorder. It's causing her to lose the ability to speak, and by her next birthday, she might not be able to talk, eat or walk on her own. By 10 years old, most children with the disease are wheelchair bound and need around-the-clock care.
Eliza has one shot at surviving – a clinical drug trial. Over two years, the family raised the $2.5 million needed to get the drug production started. Through a GoFundMe page, as well as traditional fundraising, the family met their goal last December. But what came next has proven to be even more difficult than raising the large sum of money.
The family has chosen to live in isolation to prevent Eliza from getting sicker – even the common cold can accelerate her symptoms. It's also crucial that she doesn't develop antibodies to a particular, common virus that could eliminate her from the study.
"Her body would then reject the gene therapy," Glenn told PEOPLE in July. "So when the trial happens, she wouldn't be able to take part in it. We are not going to risk that."
So the rare times that visitors come over to visit Eliza, Cara, Glenn and their 8-year-old son Beckham, they have to wear a mask and gloves.
Inside the home that has become their safe haven, the O'Neill's are creative and playful. Eliza, who is starting to forget words she always knew and can't easily put sentences together, asks her parents to show her pictures of different animals on the Internet.
Although Beckham is a trooper and understands that his family has gone to extreme measures to try and save his sisters life, he can't wait to visit Lego Land – and is even excited to walk down the aisle of a grocery store.
As they wait for the drug trial to begin, the family only occasionally goes outside, and only to isolated locations where they don't interact with anyone else.
"Last week we went to this state park and had a picnic on this bridge that Eliza calls 'troll bridges' because that's what they call it on Dora the Explorer," Glenn says.
"For just a moment we forgot that our daughter is slipping away," he says. "We will never give up and we will definitely take advantage of every second we have with her."
http://www.people.com/article/oneill-family-quaratines-themselves-saving-daughters-life
Courtesy of my daughter
It's the 453rd reminder of how many days he and his family have been living in self-imposed quarantine. "We are just trying to save her life," Glenn, 42, tells PEOPLE of his daughter, Eliza. "The piece of paper reminds us how far we have come and how much further we need to get it."
Eliza O'Neill, a bubbly 5-year-old, was diagnosed in July, 2013, with Sanfilippo syndrome, type A – the most severe form of the rare genetic disorder. It's causing her to lose the ability to speak, and by her next birthday, she might not be able to talk, eat or walk on her own. By 10 years old, most children with the disease are wheelchair bound and need around-the-clock care.
Eliza has one shot at surviving – a clinical drug trial. Over two years, the family raised the $2.5 million needed to get the drug production started. Through a GoFundMe page, as well as traditional fundraising, the family met their goal last December. But what came next has proven to be even more difficult than raising the large sum of money.
The family has chosen to live in isolation to prevent Eliza from getting sicker – even the common cold can accelerate her symptoms. It's also crucial that she doesn't develop antibodies to a particular, common virus that could eliminate her from the study.
"Her body would then reject the gene therapy," Glenn told PEOPLE in July. "So when the trial happens, she wouldn't be able to take part in it. We are not going to risk that."
So the rare times that visitors come over to visit Eliza, Cara, Glenn and their 8-year-old son Beckham, they have to wear a mask and gloves.
Inside the home that has become their safe haven, the O'Neill's are creative and playful. Eliza, who is starting to forget words she always knew and can't easily put sentences together, asks her parents to show her pictures of different animals on the Internet.
Although Beckham is a trooper and understands that his family has gone to extreme measures to try and save his sisters life, he can't wait to visit Lego Land – and is even excited to walk down the aisle of a grocery store.
As they wait for the drug trial to begin, the family only occasionally goes outside, and only to isolated locations where they don't interact with anyone else.
"Last week we went to this state park and had a picnic on this bridge that Eliza calls 'troll bridges' because that's what they call it on Dora the Explorer," Glenn says.
"For just a moment we forgot that our daughter is slipping away," he says. "We will never give up and we will definitely take advantage of every second we have with her."
http://www.people.com/article/oneill-family-quaratines-themselves-saving-daughters-life
Courtesy of my daughter
Wednesday, August 19, 2015
Bedtime stories for young brains
A little more than a year ago, the American Academy of Pediatrics issued a policy statement saying that all pediatric primary care should include literacy promotion, starting at birth.
That means pediatricians taking care of infants and toddlers should routinely be advising parents about how important it is to read to even very young children. The policy statement, which I wrote with Dr. Pamela C. High, included a review of the extensive research on the links between growing up with books and reading aloud, and later language development and school success.
But while we know that reading to a young child is associated with good outcomes, there is only limited understanding of what the mechanism might be. Two new studies examine the unexpectedly complex interactions that happen when you put a small child on your lap and open a picture book.
See: http://well.blogs.nytimes.com/2015/08/17/bedtime-stories-for-young-brains/?smprod=nytcore-ipad&smid=nytcore-ipad-share&_r=0
Hutton JS, Horowitz-Kraus T, Mendelsohn AL, DeWitt T, Holland SK; C-MIND
Authorship Consortium. Home Reading Environment and Brain Activation in Preschool
Children Listening to Stories. Pediatrics. 2015 Aug 10. pii: peds.2015-0359.
[Epub ahead of print]
Parent-child reading is widely advocated to promote cognitive development, including in recommendations from the American Academy of Pediatrics to begin this practice at birth. Although parent-child reading has been shown in behavioral studies to improve oral language and print concepts, quantifiable effects on the brain have not been previously studied. Our study used blood oxygen level-dependent functional magnetic resonance imaging to examine the relationship between home reading environment and brain activity during a story listening task in a sample of preschool-age children. We hypothesized that while listening to stories, children with greater home reading exposure would exhibit higher activation of left-sided brain regions involved with semantic processing (extraction of meaning).
Nineteen 3- to 5-year-old children were selected from a longitudinal study of normal brain development. All completed blood oxygen level-dependent functional magnetic resonance imaging using an age-appropriate story listening task, where narrative alternated with tones. We performed a series of whole-brain regression analyses applying composite, subscale, and individual reading-related items from the validated StimQ-P measure of home cognitive environment as explanatory variables for neural activation.
Higher reading exposure (StimQ-P Reading subscale score) was positively correlated (P < .05, corrected) with neural activation in the left-sided parietal-temporal-occipital association cortex, a "hub" region supporting semantic language processing, controlling for household income.
In preschool children listening to stories, greater home reading exposure is positively associated with activation of brain areas supporting mental imagery and narrative comprehension, controlling for household income. These neural biomarkers may help inform eco-bio-developmental models of emergent literacy.
Montag JL, Jones MN, Smith LB. The Words Children Hear: Picture Books and the
Statistics for Language Learning. Psychol Sci. 2015 Aug 4. pii: 0956797615594361.
[Epub ahead of print]
Young children learn language from the speech they hear. Previous work suggests that greater statistical diversity of words and of linguistic contexts is associated with better language outcomes. One potential source of lexical diversity is the text of picture books that caregivers read aloud to children. Many parents begin reading to their children shortly after birth, so this is potentially an important source of linguistic input for many children. We constructed a corpus of 100 children's picture books and compared word type and token counts in that sample and a matched sample of child-directed speech. Overall, the picture books contained more unique word types than the child-directed speech. Further, individual picture books generally contained more unique word types than length-matched, child-directed conversations. The text of picture books may be an important source of vocabulary for young children, and these findings suggest a mechanism that underlies the language benefits associated with reading to children.
Courtesy of a colleague
That means pediatricians taking care of infants and toddlers should routinely be advising parents about how important it is to read to even very young children. The policy statement, which I wrote with Dr. Pamela C. High, included a review of the extensive research on the links between growing up with books and reading aloud, and later language development and school success.
But while we know that reading to a young child is associated with good outcomes, there is only limited understanding of what the mechanism might be. Two new studies examine the unexpectedly complex interactions that happen when you put a small child on your lap and open a picture book.
See: http://well.blogs.nytimes.com/2015/08/17/bedtime-stories-for-young-brains/?smprod=nytcore-ipad&smid=nytcore-ipad-share&_r=0
Hutton JS, Horowitz-Kraus T, Mendelsohn AL, DeWitt T, Holland SK; C-MIND
Authorship Consortium. Home Reading Environment and Brain Activation in Preschool
Children Listening to Stories. Pediatrics. 2015 Aug 10. pii: peds.2015-0359.
[Epub ahead of print]
Abstract
BACKGROUND AND OBJECTIVES:
METHODS:
RESULTS:
CONCLUSIONS:
---------------------------------------------------------------------------------------------------
Statistics for Language Learning. Psychol Sci. 2015 Aug 4. pii: 0956797615594361.
[Epub ahead of print]
Abstract
Management of infantile seizures
Wilmshurst JM, Gaillard WD, Vinayan KP, Tsuchida TN, Plouin P, Van Bogaert P,
Carrizosa J, Elia M, Craiu D, Jovic NJ, Nordli D, Hirtz D, Wong V, Glauser T,
Mizrahi EM, Cross JH. Summary of recommendations for the management of infantile
seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia.
2015 Aug;56(8):1185-97.
Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or "state of the art" interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video-EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile-onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short-term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short-term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long-term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits.
Carrizosa J, Elia M, Craiu D, Jovic NJ, Nordli D, Hirtz D, Wong V, Glauser T,
Mizrahi EM, Cross JH. Summary of recommendations for the management of infantile
seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia.
2015 Aug;56(8):1185-97.
Abstract
Cannabidiol and clobazam interactions
Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between
clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015
Aug;56(8):1246-51.
Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article.
Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored.
We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction.
Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015
Aug;56(8):1246-51.
Abstract
OBJECTIVE:
METHODS:
RESULTS:
SIGNIFICANCE:
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