Thursday, January 31, 2019

Acute flaccid myelitis paralysis reversed in new surgery

Saltzman EB, Rancy SK, Sneag DB, Feinberg Md JH, Lange DJ, Wolfe SW. Nerve Transfers for Enterovirus D68-Associated Acute Flaccid Myelitis: A Case Series. Pediatr Neurol. 2018 Nov;88:25-30.

Acute flaccid myelitis is associated with enterovirus D68 -induced inflammation and destruction of cervical anterior horn cells. To date, no medical intervention has altered the disease course.

We report two pediatric patients who were treated with nerve transfer in three limbs with sustained upper extremity neuropathy. Postoperative outcomes included muscle strength, graded on the British Medical Research Council (BMRC) scale, range of motion, and electromyography.

Two years postoperatively, Patient 1 had improved elbow flexion to BMRC grade 4+, 125° of flexion, and discrete to decreased motor unit recruitment in targeted muscles. Twenty-one months postoperatively, Patient 2 demonstrated right brachialis flexion to BMRC grade 4+/5 and deltoid firing with simultaneous pectoralis major recruitment, and limited but active flexor digitorum profundus flexion.

Both patients continue to demonstrate functional recovery two years postoperatively. These outcomes suggest a promising reconstructive technique for this emerging and devastating viral endemic.
“We were most surprised that no viable treatment strategy existed to improve the function of patients affected by AFM,” study author Scott Wolfe, MD, told Rare Disease Report®. “We believe that surgical techniques developed for treatment of brachial plexus palsy in children and adults can be used successfully to restore function to paralyzed muscles in affected patients.”

Both of the pediatric patients involved in the case report had demonstrated significant or complete denervation of muscles. The investigators performed nerve transfers in 3 limbs and then measured muscle strength postoperatively in accordance with the British Medical Research Council scale, plus range of motion, and electromyography (EMG) testing.

The first patient, a 12-year-old male from New York State, presented with right greater than upper left extremity weakness. Eventually, he developed bilaterial upper extremity weakness, which progressed to the fingers and neck. He was brought to HSS after 8 months with the disease to undergo surgery, which involved the transfer of donor muscles from other sections of his own body.

After 3 months postop, the patient demonstrated “promising functional returns,” and by 2 years postop, EMG showed full biceps motor unit recruitment. After 35 months, the patient improved to full elbow flexation and shoulder rotation to 135 degrees.

The second patient was a 14-year-old Illinois female who experienced 9 months of upper extremity weakness followed by conjunctivitis and gastroenteritis. She was admitted to intensive care after developing severe neck pain that progressed to flaccid quadriparesis and respiratory failure. She underwent bilateral nerve transfer surgeries using donor muscle tissue from her own body.

After 10 months postop, she regained full right elbow flexation. After 21 months, EMG testing showed discrete recruitment of all 3 deltoid heads that were treated. After 32 months, she achieved near normal right brachialis strength and full recovery in her elbow’s range of motion. The study authors reported she had no functional loss related to the nerve transfers and maintained normal medial nerve function and shoulder adduction.

“With increased numbers of surgically treated patients, we can document outcomes on a larger scale and identify which nerve and tendon transfers offer the best hope for patients with AFM,” Wolfe concluded.

Tuesday, January 29, 2019

Syndromes with very low risk of acute prolonged seizures

Bast T. Syndromes with very low risk of acute prolonged seizures. Epileptic Disord. 2014 Oct;16 Spec No 1:S96-102.

The provision of rescue medication is an important component in the treatment of epilepsy. An intervention within five to ten minutes in the case of an acute prolonged seizure may preserve the patient from status epilepticus (SE). However, the risk of convulsive SE (CSE) differs markedly between patients depending on individual factors. This report summarizes the literature on risk factors for CSE in children with epilepsy and adolescents, and discusses the hypothesis that some electroclinical syndromes engender a very low risk of CSE. The most important risk factor for SE is the history of a previous event. The longer a patient lives without SE, the lower the risk will be. CSE occurs significantly less frequently in idiopathic epilepsies compared to epilepsies with symptomatic or unknown aetiology. It is very rarely observed in patients with (non-encephalopathic) idiopathic generalised epilepsies, i.e. childhood absence epilepsy or juvenile myoclonic epilepsy. However, non-compliance or inappropriate treatment may trigger CSE in these syndromes. A very low risk can be assumed for children with Rolandic epilepsy, while CSE occurs in a considerable percentage of patients with Panayiotopoulos syndrome. Although the risk of CSE in otherwise normal children with cryptogenic focal epilepsy is uncertain, it is presumably low under successful continuous medication. In conclusion, the choice for or against the prescription of rescue medication remains an individual decision. Consequently, for several electroclinical syndromes, a per se provision of rescue medication does not appear justified.

Monday, January 28, 2019

Asparagine synthetase deficiency

Gupta N, Tewari VV, Kumar M, Langeh N, Gupta A, Mishra P, Kaur P, Ramprasad V, Murugan S, Kumar R, Jana M, Kabra M. Asparagine Synthetase deficiency-report of a novel mutation and review of literature. Metab Brain Dis. 2017 Dec;32(6):1889-1900.

Asparagine synthetase deficiency is a rare inborn error of metabolism caused by a defect in ASNS, a gene encoding asparagine synthetase. It manifests with a severe neurological phenotype manifesting as severe developmental delay, congenital microcephaly, spasticity and refractory seizures. To date, nineteen patients from twelve unrelated families have been identified. Majority of the mutations are missense and nonsense mutations in homozygous or compound heterozygous state. We add another case from India which harbored a novel homozygous missense variation in exon 11 and compare the current case with previously reported cases.

Ben-Salem S, Gleeson JG, Al-Shamsi AM, Islam B, Hertecant J, Ali BR, Al-Gazali L. Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay. Metab Brain Dis. 2015 Jun;30(3):687-94.

Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (ASNS, EC, particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the ASNS gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the ASNS gene to four. This finding extends the ASNS pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.

Alrifai MT, Alfadhel M. Worsening of Seizures After Asparagine Supplementation in a Child with Asparagine Synthetase Deficiency. Pediatr Neurol. 2016 May;58:98-100.

Asparagine synthetase deficiency is an autosomal recessive neurometabolic disorder characterized clinically by severe congenital microcephaly, global developmental delay, intractable epilepsy, and motor impairment in the form of spastic quadriparesis. Diagnosis is confirmed by findings of low cerebral spinal fluid or plasma asparagine in addition to a mutation of the subsequently in ASNS gene. There is no documented trial of asparagine as a treatment for this disorder.

We present a child with asparagine synthetase deficiency whose mental status improved slightly from a vegetative state to a minimally conscious state after starting asparagine supplementation. He subsequently became irritable, developed sleep disturbance, and experienced worsening seizures, requiring discontinuation of the asparagine supplements.

Asparagine supplementation may be not effective in controlling the seizures in asparagine synthetase deficiency, and it is likely to make them worse.

Friday, January 25, 2019

Tocilizumab treatment for new onset refractory status epilepticus (NORSE)

Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol. 2018 Dec;84(6):940-945.

We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.

Seizures were aborted in six of seven patients with new-onset refractory status epilepticus (NORSE) within three days after treatment with the interleukin-6 receptor inhibitor tocilizumab (Actemra), according to a new case series report published online November 8 in Annals of Neurology. All seven NORSE patients had been unresponsive to conventional immunotherapy therapies and rituximab.

NORSE is a rare condition characterized by new onset of refractory status epilepticus in a patient without epilepsy or another relevant preexisting neurologic disorder, without a clear acute or active structural, toxic, or metabolic cause.

“These are patients without any preexisting history of epilepsy who [suddenly] go into status epilepticus,” said Jeffrey W. Britton, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN, who was not involved with the study. “The mortality and morbidity of refractory status epilepticus is very high, and for survivors the functional consequences can be significant.”

Between 20- and 30-percent of patients with NORSE do not survive, and most survivors have lifelong epilepsy as well as significant neurological sequelae, according to a study published earlier this year in Epilepsia…

In the current study, three of the patients (43 percent) had good or fair functional outcomes, defined as a having score greater than 3 on the modified Rankin Scale at discharge and the use of antiepileptic drugs at the last follow-up.

The study, led by Jin-Sun Jun, MD, professor of neurology at the Kyungpook National University School of Medicine and colleagues at Seoul National University Hospital in South Korea, found that some of those on tocilizumab had severe adverse events, however. Two patients experienced adverse events of grade 3 or higher: A 22-year-old man had pneumonia and a 19-year-old woman died after experiencing a worsening of preexisting sepsis. Other adverse events included leukopenia (grade 2, n=3) and diarrhea (grade 2, n=1).

The authors acknowledged some significant limitations to the study, including heterogeneity in both the patients' pretreatment histories and the tocilizumab regimens they were given, which could limit the ability to generalize based on their results.

The authors also noted that while three of the seven patients had good or fair outcomes after discharge, those outcomes were not better than those reported in a previous large case series reported in Neurology in 2015…

Commenting on the study findings, Dr. Britton of the Mayo Clinic pointed out that four of the seven patients in the case series had significant elevations of interleukin-6, the target of tocilizumab, which provides some potential mechanistic evidence as to why this particular drug may have worked. He cited his own center's recent experience with a pediatric FIRES patient refractory to standard treatment, whose analysis of cerebrospinal fluid interleukin levels suggested a potential response to the IL-1 antagonist anakinra (Kineret), a rheumatoid arthritis medication. “She responded well and made an excellent recovery,” Dr. Britton said….

But the experts cautioned that this study should not necessarily be used as justification for wide-scale use of tocilizumab in NORSE cases. “You're in such dire straits with these patients [that] I think the temptation, based on this article, is going to be to use this earlier, and in a more indiscriminate manner,” said Dr. Britton. “These inflammatory markers are not widely available, and not every lab is going to be able to do them for the clinician at the bedside.”…

There was a hint in this study that those who got tocilizumab earlier in the course of their illness responded better than those who got it later. You don't want to wait several weeks before initiating immunotherapy, as it looks like doing so earlier is much more effective, based on this series and others.”

Dr. Schmitt advised caution, however, pointing to the severity of the adverse events in the case series. “As a rule, people with NORSE don't die from epilepsy per se; they die from complications related to their long stays in the intensive care unit, such as venous thromboembolism and respiratory complications. If these medications potentially worsen the risk of these infections, we might be treating their status epilepticus effectively but at the same time making them more susceptible to blood-borne pathogens and other types of illness. So I would be extremely cautious, given those results, about treating a patient with those medications if they were known to have any type of ongoing infection.”

Five of the seven patients had been treated with IVIg, steroids, and rituximab, while the other two had been treated with IVIg plus steroids. “Additive immune suppression really increases a patient's chance of developing dangerous opportunistic infections,” Dr. Schmitt said. “When do you try it? That's the challenge. Although patients who got this this medication earlier appeared to do better, I would be a little nervous about the significant risks of adverse events. I would say this medication might be a third-line alternative to cyclophosphamide, which some people have been using as a third-line option and which is also associated with a significant risk of immunosuppression complications. There is relative equipoise between those two drugs, but I would not use this agent before methylprednisolone or IVIg.”,_Tocilizumab_Shows_Promise.2.aspx

Thursday, January 24, 2019

Williams v. Quest Diagnostics, Inc.

Christian Millare was born in August 2005 and beginning at the age of 4 months started having seizures. His doctors treated his seizures with sodium channel inhibitor medications: oxcarbazepine (Trileptal®), carbamazepine (Tegretol®), and lamotrigine (Lamictal®). These are standard treatments for epileptic seizures not caused by Dravet syndrome (SMEI). In January 2007, Christian’s DNA was sent to Athena Diagnostics (a subsidiary of Quest starting in 2011) for a DNA analysis of the SCN1A gene—that is, the detection and diagnosis of any DNA variants within the SCN1A gene. DNA mutations in SCN1A are associated with a spectrum of epilepsy phenotypes, the most severe being Dravet syndrome. For patients with SCN1A mutations, sodium channel inhibitor medications are to be avoided because they exacerbate the seizures. The DNA sequencing of Christian’s DNA took place in May 2007. The results were sent to the ordering physician, John Shoffner, on June 30, 2007. This report indicated that Christian possessed a DNA variant in the SCN1A gene that was classified as a “variant of unknown significance” or VUS (i.e., not specifically known to be either pathogenic or benign). Relying on the information in this report (which did not identify any DNA variants as being pathogenic or warn of any treatments to avoid), Christian’s doctors continued to treat him with increasing doses of multiple sodium channel inhibitor medications. Athena did not issue a copy of the June 2007 report directly to the patient or the patient’s family. Christian’s condition worsened, even as doses of the sodium channel inhibitor medications were increased in attempts to manage his seizures. Christian suffered a severe and ultimately fatal seizure resulting in his death on January 5, 2008.

His mother, Amy Williams, sued Athena and Quest, its parent company, in a South Carolina state court in March 2016. The defendants were able to “remove” the case to the South Carolina federal court because the plaintiff and defendants are citizens of different states. Nonetheless, South Carolina state law will continue to apply.

The complaint alleges that Athena was negligent and breached the applicable standard of care by (1) failing to provide a genetic confirmation that Christian had Dravet syndrome and (2) failing to adhere to its own DNA variant classification criteria. The alleged negligent misclassification of Christian’s DNA variant originates from the fact that in 2007, Christian’s DNA variant had been reported, studied, and known in a patient with Dravet syndrome. Specifically, a genotype-phenotype association between his variant and Dravet syndrome had been established in two clinical publications, Berkovic et al., 2006, and Harkin et al., 2007. Per Athena’s DNA variant classification criteria as defined in the June 2007 report, the requirement for deeming a variant to be a “known disease-associated mutation” was whether it was reported in the literature to be associated with the disease. Thus, the plaintiff alleges, the existence of Berkovic et al., 2006 and Harkin et al., 2007 made Athena’s classification of Christian’s variant as VUS (i.e., “has not been correlated with clinical presentation and/or pathology in the current literature”) demonstrably false. According to the June 2007 report, “the results of this analysis cannot be definitively interpreted due to the absence of published studies correlating these variant(s) with clinical presentation and/or pathology.”

Christian’s June 2007 report was signed off by Sat Dev Batish, chief director of genetics at Athena, and also an author of the Harkin et al., 2007 publication. According to the complaint, Christian’s DNA variant was cited as an SCN1A DNA mutation that “disrupts the functioning of an assembled ion channel so as to produce an epilepsy phenotype” in a patent for SCN1A testing. This patent originated from the laboratory that produced the Berkovic et al., 2006 and Harkin et al., 2007 publications—the same laboratory that also licensed use of the patent for SCN1A testing to Athena in 2004. Thus, the information used to gain patent rights of SCN1A testing included a citation of Christian’s variant causing an epilepsy phenotype. Finally, the June 2007 report lists a manuscript that was published in 2005 as “pending,” suggesting that Athena’s integration of the biomedical literature into their DNA variant database was at least two years behind…

At the hearing, Williams’s lawyer argued that these are acts of ordinary negligence, with a three-year statute of limitations that didn’t start to run until she discovered the negligence. Williams claims she was unaware of the June 2007 report until September 2014, at which time the June 2007 report was requested and received from Athena. During this 2014 interaction with Quest/Athena, Williams learned that the variant had now been deemed disease-causing and the report would be revised. Quest/Athena subsequently issued a revised report with the new classification of “known disease-associated mutation” on January 30, 2015. Williams contends that she had no opportunity to discover the defendants’ error until she had both the June 2007 and January 2015 reports in hand. Quest/Athena argued that it doesn’t matter whether or not the plaintiff herself knew or did not know about the 2007 report, because “the actual knowledge is imputed to the principal by virtue of [her] agent’s notice”—the agent in this case being the physician, John Shoffner, who ordered the test and received the June 2007 report. Williams also contends that Athena’s failure to notify anyone of the reclassification of Christian’s DNA variant prior to January 30, 2015 was a daily, recurring failure to comply with CLIA regulations, and thus represents a continuous and ongoing injury, each instance allowing for a new claim and thus starting a new clock…

According to the complaint, Williams believes that because a genotype-phenotype association between Christian’s DNA variant and Dravet syndrome had been established in two clinical publications (Berkovic et al., 2006 and Harkin et al., 2007), the June 2007 report should have classified Christian’s mutation as a “known disease-associated mutation” rather than a VUS. The existence of these two clinical publications would apparently satisfy the requirements of a “known disease-associated mutation” per Athena’s own DNA variant classification criteria as defined in the June 2007 report. (The requirement for deeming a variant to be disease-causing was whether it was reported in the literature to be associated with the disease.) Williams further alleges that classifying Christian’s DNA variant as a VUS in 2007 was incorrect per these same DNA variant classification criteria: “Variants of unknown significance are DNA sequence variants that are detected reproducibly, but have not been correlated with clinical presentation and/or pathology in the current literature.”

At the hearing Athena’s lawyer argued that “the patient that is identified (in Berkovic et al., 2006 and Harkin et al., 2007) as having the same genetic mutation” had, in both papers, a de novo” mutation. That is, the mutation was not inherited but instead arose during cell division of egg or sperm or early embryonic development. The defense further contended that parental testing is required to determine whether a mutation is de novo, and thus “within the classification that was in those two published reports because the patients in those reports had a de novo mutation.” According to this argument, Athena has no way to know “whether or not this serious disease is present in this mutation unless we test the parents.” The lawyer’s point was that Athena could not have known whether Christian’s mutation was de novo—and thus the same as the mutation in the published papers—because his parent did not undergo genetic testing. As noted above, however, Williams contends that, because she was unaware of the June 2007 report, she was unaware that testing of the biological parents (de novo determination) was recommended.

Athena’s lawyer pointed to patient #15 on Supplement Table 2 of Harkin et al., 2007 (a female who possessed the same mutation as Christian whose mutation was confirmed to be de novo) to illustrate that a conclusive diagnosis could be reached only by additional parental testing and de novo determination. It is intriguing that the next patient listed (#16), along with thirteen other patients on this table, had the same classification as patient number #15 but de novo status was not determined. According to Harkin et al., 2007, “in cases with missense changes, where DNA from parents is unavailable…the case for pathogenicity rests on circumstantial evidence provided by evolutionary conservation of protein structure.” Further, if parental testing was never done on Christian because his parents were unaware of this recommendation, and de novo determination was required for the DNA variant to be classified as a “known disease-associated mutation,” it is hard to understand how and why his DNA variant was reclassified to a “known disease-association mutation” sometime after the June 2007 report and before September 29, 2014…

Judge Seymour wanted to know why the 2007 report was revised. Athena’s lawyer said that “there was an update to the classification of the mutation in Athena’s database,” and that “as soon as the information became known that it was applicable to this situation, the update was provided to the requesting individual.” Athena’s lawyer further explained,

“the plaintiff’s genetic counselor called Athena in 2014 and asked Athena to re-look up the variant. Athena did so and saw that the variant, the mutation, had been reclassified since then in its database, and based on additional information that was available since June of 2007—remember, this is an incredibly fast-paced field—more than seven years later when the variant was looked up in the database to see how it’s classified. Classifications of variants do change based on new information, and that is what happened here. It’s not a reclassification based on an error. It was just based on new information” [Of note, according to the complaint, Athena was contacted in 2014 to in order to obtain the 2007 report for the first time, not to “re-look up” a variant.]

Athena’s lawyer did not explain what “new information” was obtained between June 2007 and September 2014 that resulted in the reclassification of Christian’s DNA variant (1237T>A, Y413N) from a “variant of unknown significance” to a “known disease-associated mutation.” According to the January 2015 report, “analysis of this individual’s SCN1A gene identified a DNA sequence variant that has been reported in the literature to be associated with SMEI or SMEB, the severe phenotypes associated with SCN1A mutations.”

Monday, January 14, 2019

CACNA1E mutations

Inspired by a patient who survived almost 11 months.

Helbig KL, Lauerer RJ, Bahr JC, Souza IA, Myers CT, Uysal B, Schwarz N, Gandini MA, Huang S, Keren B, Mignot C, Afenjar A, Billette de Villemeur T, Héron D, Nava C, Valence S, Buratti J, Fagerberg CR, Soerensen KP, Kibaek M, Kamsteeg EJ, Koolen DA, Gunning B, Schelhaas HJ, Kruer MC, Fox J, Bakhtiari S, Jarrar R, Padilla-Lopez S, Lindstrom K, Jin SC, Zeng X, Bilguvar K, Papavasileiou A, Xin Q, Zhu C, Boysen K, Vairo F, Lanpher BC, Klee EW, Tillema JM, Payne ET, Cousin MA, Kruisselbrink TM, Wick MJ, Baker J, Haan E, Smith N, Corbett MA, MacLennan AH,
Gecz J, Biskup S, Goldmann E, Rodan LH, Kichula E, Segal E, Jackson KE, Asamoah A, Dimmock D, McCarrier J, Botto LD, Filloux F, Tvrdik T, Cascino GD, Klingerman S, Neumann C, Wang R, Jacobsen JC, Nolan MA, Snell RG, Lehnert K, Sadleir LG, Anderlid BM, Kvarnung M, Guerrini R, Friez MJ, Lyons MJ, Leonhard J, Kringlen G, Casas K, El Achkar CM, Smith LA, Rotenberg A, Poduri A, Sanchis-Juan A, Carss KJ, Rankin J, Zeman A, Raymond FL, Blyth M, Kerr B, Ruiz K, Urquhart J, Hughes I, Banka S; Deciphering Developmental Disorders Study, Hedrich UBS, Scheffer IE, Helbig I, Zamponi GW, Lerche H, Mefford HC. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders. 

Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D, De Jonghe P, Guerrini R, Helbig KL, Koeleman BPC, Kosmicki JA, Linnankivi T, May P, Muhle H, Møller RS, Neubauer BA, Palotie A, Pendziwiat M, Striano P, Tang S, Wu S; EuroEPINOMICS RES Consortium, Poduri A, Weber YG, Weckhuysen S, Sisodiya SM, Daly MJ, Helbig I, Lal D, Lemke JR. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet. 2018 Jul;50(7):1048-1053.

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

Wednesday, January 2, 2019

Etiologies and yield of diagnostic testing in children presenting to the emergency department with altered mental status

Button K, Capraro A, Monuteaux M, Mannix R. Etiologies and Yield of Diagnostic Testing in Children Presenting to the Emergency Department with Altered Mental Status. J Pediatr. 2018 Sep;200:218-224.e2.


To identify etiologies of altered mental status in pediatric patients presenting to the emergency department (ED) and to characterize the yield of diagnostic testing in these patients.

Retrospective chart review of children aged 1-17 years presenting to a pediatric tertiary care ED between December 31, 2013 and December 31, 2014 with a chief complaint or International Classification of Disease, Ninth Edition code of altered mental status. The primary outcome was the etiology, defined as "immediate diagnosis" if the etiology was known in triage, "definitely established" if established by physical examination and abnormal laboratory results, imaging, or electrocardiogram findings, "probable" if the etiology was highly suspected in the ED but not confirmed with positive test results, or "unknown." The secondary outcome was testing utilization and contribution to the diagnosis.

Three hundred thirty-six eligible subjects were identified; mean age of 9 years (±6 years). The etiology of altered mental status was immediately established in 114 subjects (34%, 95% CI 29, 39). Among the remaining eligible subjects (N = 222), a definite or probable cause of altered mental status was identified in 82% (N = 182, 95% CI 76, 86) of cases and the etiology remained "unknown" in 18% (N = 40, 95% CI 14, 24). Only 10% of diagnostic tests performed were abnormal and contributed to a diagnosis. The median number of diagnostic tests per patient was 6 (IQR 3, 8).

Etiologies of altered mental status in children varied widely and often an underlying diagnosis was not found. Broad diagnostic testing was commonly performed although the overall yield was low.

From the paper:

Among all eligible subjects, including those for whom an immediate diagnosis was made, the most common etiology was neurologic, occurring in 24% (N = 79, 95% CI 19, 28) of children. Other common etiologies included toxicological (20%, N = 69, 95% CI 17, 25) and infectious (14%, N = 46, 95% CI 10, 18) conditions. Among subjects aged 1-5 years and 6-12 years, the most common overall etiology was neurologic. For subjects aged 13-17 years, the most common etiology was toxicological. Examining etiologies by age separately among the immediate and nonimmediate diagnosis groups  underscores trauma as an important etiology in the immediate diagnosis group for children ages 1-5 years (35%, N = 13) and 6-12 years (33%, N = 9,). In the nonimmediate diagnosis group, infection was the most common etiology for children 1-5 years of age (N = 17, 22%, 95% CI 14, 33) and neurologic the most common for children 6-12 years of age (N = 17, 25%, 95% CI 16, 37). Toxicological etiologies were consistently the most common among children aged 13-17 years in 

In the 222 subjects for whom the underlying etiology of altered mental status was not immediately established, the median number of diagnostic tests performed per subject was 6 (IQR 3, 8). A total of 1208 diagnostic tests were performed including laboratory testing and imaging. Laboratory tests performed in the greatest number of patients were basic chemistry (N = 186, 83%, 95% CI 78, 88), complete blood count (N = 168, 76%, 95% CI 70, 81), and liver function tests (N = 117, 53%, 95% CI 46, 59). Head CT was the most frequently performed imaging study (N = 80, 36%, 95% CI 30, 43). Diagnostic tests that most often contributed to a diagnosis (relative to how frequently they were performed) were lumbar puncture (N = 11, 42%, 95 CI 26, 61), magnetic resonance imaging/ magnetic resonance angiography brain (N = 17, 33%, 95 CI 22, 46), and head CT (N = 15, 19%, 95 CI 12, 29). Tests that contributed the least often to a diagnosis were serum liver function tests (N = 0, 0%, 95% CI 0, 3), serum lactate (N = 0, 0%, 95% CI 0, 8), ultrasound for intussusception (N = 0, 0%, 95% CI 0, 43), and electrocardiogram (N = 3, 3%, 95% CI 1, 9). Overall, 10% (N = 125) of the total number of diagnostic tests performed were abnormal and contributed to identifying an underlying diagnosis

An important take-home message is that practitioners should not be surprised to find that they can't make a diagnosis in about 1 of every 10 children presenting with altered mental status—and almost 1 out of 5 of those whose diagnosis is not immediately obvious.

Being comfortable with that fact is part of the "art of medicine."

Oculomotor response to cumulative subconcussive head impacts in US high school football players

Zonner SW, Ejima K, Fulgar CC, Charleston CN, Huibregtse ME, Bevilacqua ZW, Kawata K. Oculomotor Response to Cumulative Subconcussive Head Impacts in US High School Football Players: A Pilot Longitudinal Study. JAMA Ophthalmol. 2018 Dec 20. doi: 10.1001/jamaophthalmol.2018.6193. [Epub ahead of print]


Repetitive subconcussive head impacts in sports have emerged as a complex public health issue. Most of these head impacts remain asymptomatic yet have the potential to cause insidious neurological deficit if sustained repetitively. Near point of convergence (NPC) values have shown to reflect subclinical neuronal damage; however, the longitudinal pattern of NPC changes in association with subconcussive head impacts remains unclear.

To examine the NPC response to recurring subconcussive head impacts in a single high school football season through a series of repeated measurements.

This prospective case-series study of US varsity high school football players included baseline measurements of NPC, measurements at pregame and postgame points from 6 in-season games, and postseason follow-up measurements (a total of 14 points). An accelerometer-embedded mouthguard measured head impact frequency and magnitude from all practices and games. During the 6 games, players wore chest-strap heart rate monitors to record heart rate and estimate their excess postexercise oxygen consumption, accounting for possible physical exertion effects on NPC values.

Players participated in practices and games with no restriction.

Near point of convergence.

The 12 included players were all boys, with a mean (SD) age of 16.4 (0.5) years. A total of 8009 head impacts, 177 907 g of peak linear acceleration, and 16 123 371 rad/s2 of peak rotational acceleration were recorded from the players in a single football season. There was a significant increase in NPC over time until the middle of the season (mean [SD] NPC: baseline, 5.25 [1.49] cm; pregame 3, 6.42 [1.93] cm; P = .01), which was significantly associated with subconcussive head impact frequency and magnitude (0.02 cm per 100 g of peak linear acceleration [SE, 0.0108; 95% CI, 0.0436-0.004]; P = .01; 0.023 cm per 10 000 rad/s2 of peak rotational acceleration [SE, 0.009; 95% CI, 0.041-0.0105]; P = .02). However, NPC values began to normalize toward baseline level from midseason (mean [SD] NPC: baseline, 5.25 [1.49] cm; pregame 6, 5.75 [2.23] cm; P = .32), as supported by a significant quadratic trend (β [SE], -0.002 [0.001] cm/d; P = .003), while participants continued to incur subconcussive head impacts.

This longitudinal case series study suggests that NPC can be perturbed over the long term by subconcussive head impacts but may normalize over time. The oculomotor system may have an adaptational capacity to subclinical head impacts, yet the mechanism for such remains an open question and warrants further investigation.

Tuesday, January 1, 2019

Efficacy of stiripentol and the clinical outcome in Dravet syndrome

Pembegul Yıldız E, Ozkan MU, Uzunhan TA, Bektaş G, Tatlı B, Aydınlı N, Çalışkan M, Özmen M. Efficacy of Stiripentol and the Clinical Outcome in Dravet Syndrome. J Child Neurol. 2018 Oct 26:883073818811538. doi:10.1177/0883073818811538. [Epub ahead of print]

Dravet syndrome is a rare and progressive epileptic encephalopathy of infancy. Stiripentol reduces the seizure frequency in patients with Dravet syndrome. We evaluated the clinical characteristics of patients with Dravet syndrome and their response to stiripentol. We retrospectively collected the data of 21 patients (11 females; mean age, 8.2 years, range: 5.4-15 years) with Dravet syndrome who were treated with stiripentol in our outpatient clinic between June 2016 and June 2017. Patients with seizure reduction ≥50% were considered responders. Most of our patients had severe (47%) or moderate (33%) cognitive disabilities, although 14% had mild cognitive disability. There was a significant difference in both status epilepticus and age between the groups with normal/mild versus severe/moderate neurocognitive prognoses. Of the patients, 85.7% were using stiripentol. The mean duration of stiripentol use was 41.2 months (range: 24-64 months). In 12 patients (57%), the seizure frequency decreased by more than 50%, and 2 of them were seizure-free. Status epilepticus was not recorded after stiripentol treatment in 8 of 11 patients with status epilepticus. Despite the small sample size, our results suggest that stiripentol has a favorable efficacy. In addition, considering the absence of status epilepticus after treatment and the negative effects of status epilepticus on cognitive development, early treatment should be initiated in SD patients, for whom disease control is difficult.

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Efficacy of rufinamide in childhood refractory epilepsy

Yıldız EP, Hızlı Z, Bektaş G, Ulak-Özkan M, Tatlı B, Aydınlı N, Çalışkan M, Özmen M. Efficacy of rufinamide in childhood refractory epilepsy. Turk J Pediatr. 2018;60(3):238-243.

Rufinamide has been used as a new antiepileptic drug in the treatment of drug-resistant epilepsy, in recent years. The objective of this study was to evaluate the reliability of rufinamide and its impact on seizure frequency in patients diagnosed with drug-resistant epilepsy, where seizures could not be controlled with `classical` antiepileptic drugs. We retrospectively reviewed the data of epileptic patients who were followed up between January 2004 and December 2014 in the Pediatric Neurology Department. Patients who were diagnosed with `drug resistant epilepsy` and treated with rufinamide were evaluated. Decrease in seizure frequency and drug side effects were assessed as parameters. A total of 38 patients (14 girls, 24 boys) with a mean age of 8.5 (range, 3.5-17) years were included in the study. The mean follow-up duration was 25.5 (23-29.5) months, while the mean maximal dose of rufinamide was 32.5 (28-42) mg/kg/day. Response to treatment was assessed by the reduction in frequency of seizures. The decrease was < 50% (essentially unresponsive to treatment) in 20 patients and 5099% in 8 patients. Ten patients (26.3%) remained seizure-free. The response rate for tonic seizures was 50%. In drop/attacks seizures, this ratio was found as 73%, which was quite high. Patients with myoclonic and tonic-clonic seizures did not significantly benefit from rufinamide. The rate of patients with Lennox-Gestaut syndrome (LGS) who responded very well (reduction in seizure frequency > 50%) was 55.5%. In the LGS group, patients with drop/attacks showed the best response to treatment. Rufinamide was not effective in two patients diagnosed with Dravet syndrome. Rufinamide can be safely used in pediatric patients who use multiple antiepileptic drugs and are unresponsive to the treatment. It was seen to be effective especially in patients diagnosed with LGS and drop/attacks types of seizures.

Clinical characteristics and risk factors for poor outcome in infants less than 90 days of age with bacterial meningitis

Okike IO, Ladhani SN, Johnson AP, Henderson KL, Blackburn RM, Muller-Pebody B, Cafferkey M, Anthony M, Ninis N, Heath PT; neoMen Study Group. Clinical Characteristics and Risk Factors for Poor Outcome in Infants Less Than 90 Days of Age With Bacterial Meningitis in the United Kingdom and Ireland. Pediatr Infect Dis J. 2018 Sep;37(9):837-843.

To describe the clinical characteristics and risk factors associated with poor outcome in infants <90 days of age with bacterial meningitis.

Prospective, enhanced, national population-based active surveillance for infants <90 days of age with bacterial meningitis in the United Kingdom and Ireland between July 2010 and July 2011. Infants were identified through the British Paediatric Surveillance Unit, laboratory surveillance and meningitis charities.

Clinical details was available for 263 of 298 (88%) infants where a bacterium was identified, 184 (70%) were born at term. Fever was reported in 143 (54%), seizures in 73 (28%), bulging fontanelle in 58 (22%), coma in 15 (6%) and neck stiffness in 7 (3%). Twenty-three (9%) died and 56/240 (23%) of the survivors had serious central nervous system complications at discharge. Temperature instability [odds ratio (OR), 2.99; 95% confidence interval (CI): 1.21-7.41], seizures (OR, 7.06; 95% CI: 2.80-17.81), cerebrospinal fluid protein greater than the median concentration (2275 mg/dL; OR, 2.62; 95% CI: 1.13-6.10) and pneumococcal meningitis (OR, 4.83; 95% CI: 1.33-17.58) were independently associated with serious central nervous system complications while prematurity (OR, 5.84; 95% CI: 2.02-16.85), low birthweight (OR, 8.48; 95% CI: 2.60-27.69), coma at presentation (OR, 31.85; 95% CI: 8.46-119.81) and pneumococcal meningitis (OR, 4.62; 95% CI: 1.19-17.91) were independently associated with death.

The classic features of meningitis were uncommon. The presentation in young infants is often nonspecific, and only half of cases presented with fever. A number of clinical and laboratory factors were associated with poor outcomes; further research is required to determine how knowledge of these risk factors might improve clinical management and outcomes.

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