Tuesday, March 31, 2020

Predicting recovery and outcome after pediatric stroke

Ryan J. Felling,  Mubeen F. Rafay,  Timothy J. Bernard,  Jessica L. Carpenter  Nomazulu Dlamini  Sahar M. A. Hassanein  Lori C. Jordan  Michael, J. Noetzel,  Michael J. Rivkin, Kevin A. Shapiro,  Mahmoud Slim,  Gabrielle de Veber,  International Pediatric Stroke Study Group.  Predicting Recovery and Outcome After Pediatric Stroke: Results from the International Pediatric Stroke Study.  Ann Neurol First published:25 March 2020 https://doi.org/10.1002/ana.25718


To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke.    

We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with two-year follow-up after arterial ischemic stroke.  Outcomes were defined at discharge by clinician grading and at two years by Pediatric Stroke Outcome Measure (PSOM).  Demographic, clinical, and radiologic outcome predictors were examined.  We defined changes in outcome from discharge to two years as recovery (improved outcome), emerging deficit (worse outcome), or no change.   

Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients.  Moderate to severe neurological impairment was present in 9.4% of neonates vs 48.8% of children at discharge compared to 8.0% vs 24.7% after two years.  Predictors of poor outcome included age between 28 days and one year (compared to neonates, OR 3.58, p<0.05), underlying chronic disorder (OR 2.23, p<0.05), and involvement of both small and large vascular territories (OR 2.84, p<0.05).  Recovery patterns differed, with emerging deficits more common in children under one year of age (p<0.05). 

Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common.  Age between 28 days and one year appears to be a particularly vulnerable period.  Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke.

Courtesy of:  https://www.mdlinx.com/journal-summaries/stroke/2020/03/27/7631990?spec=neurology

Monday, March 30, 2020

BRAT1 encephalopathy

Scheffer IE, Boysen KE, Schneider AL, Myers CT, Mehaffey MG, Rochtus AM, Yuen YP, Ronen GM, Chak WK, Gill D, Poduri A, Mefford HC. BRAT1 encephalopathy: a recessive cause of epilepsy of infancy with migrating focal seizures. Dev Med Child Neurol. 2019 Dec 23. doi: 10.1111/dmcn.14428. [Epub ahead of print]

Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling.

Burgess R, Wang S, McTague A, Boysen KE, Yang X, Zeng Q, Myers KA, Rochtus A, Trivisano M, Gill D; EIMFS Consortium, Sadleir LG, Specchio N, Guerrini R, Marini C, Zhang YH, Mefford HC, Kurian MA, Poduri AH, Scheffer IE. The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. Ann Neurol. 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619.


Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort.

Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study.

We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months.

We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking.

Szymańska K, Laure-Kamionowska M, Szczałuba K, et al. Clinico-pathological correlation in case of BRAT1 mutation. Folia Neuropathol. 2018;56(4):362–371. doi:10.5114/fn.2018.80870

The clinical picture of BRCA1-associated protein required for ATM activation-1 (BRAT1) comprises retractable early-onset epileptic encephalopathy, progressive microcephaly, and early demise. Both, inter- and intrafamilial variations of features of BRAT1-associated disease have been described. Here, the familial case of a brother and sister with homozygous pathogenic variants in BRAT1 is presented with special emphasis on differences in seizure type/onset and central nervous system lesions. The neuropathology is extensively discussed and hypotheses put forward that may shed light on etiology of brain symptomatology within the context of BRAT1 mutations.

Horn D, Weschke B, Knierim E, et al. BRAT1 mutations are associated with infantile epileptic encephalopathy, mitochondrial dysfunction, and survival into childhood. Am J Med Genet A. 2016;170(9):2274–2281. doi:10.1002/ajmg.a.37798

We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G>A) in one affected child via next-generation sequencing of the disease-associated genome followed by phenotype-driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice-site mutation (c.1134+1G>A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1-associated phenotype.

SATB2-associated syndrome

Zarate YA, Kaylor J, Fish J. SATB2-Associated Syndrome. 2017 Oct 12. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK458647/


SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.

The diagnosis of SATB2-associated syndrome (SAS) is established in a proband by detection of one of the following: A heterozygous intragenic SATB2 pathogenic variant (61%). A heterozygous deletion at chromosome 2q33.1 that includes SATB2 (22%). An intragenic deletion or duplication of SATB2 (9%). A chromosome translocation with a chromosome 2q33.1 breakpoint that disrupts SATB2 (8%).

Treatment of manifestations: Treatment is symptomatic. Nutritional support for feeding difficulties and management by a cleft/craniofacial team for those with palatal anomalies early in life. Early referral for developmental support/special education; standard treatment for dental anomalies, sleep disturbance, skeletal anomalies, seizure disorders, genitourinary anomalies, strabismus and refractive errors, and congenital heart defects. Surveillance: Evaluation of nutritional status, growth, and developmental progress at each visit; routine monitoring by a neurologist for those with epilepsy; annual sleep study in those with a history of sleep disturbance; evaluation for scoliosis/spine deformity at each visit and consideration of screening for osteopenia; routine evaluations by dentistry and ophthalmology.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a de novo genetic event. In two families, parental mosaicism seemed likely (given recurrence of SAS in sibs and failure to detect the genetic alteration in parental blood samples).To date, individuals with SAS are not known to reproduce. Once an SATB2 intragenic pathogenic variant, a 2q33.1 deletion that includes SATB2, or a chromosome translocation affecting SATB2 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Zarate YA, Fish JL. SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am J Med Genet A. 2017 Feb;173(2):327-337. doi:10.1002/ajmg.a.38022.

The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations.

Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D, Ben Haim L, Young AMH, Batiuk MY, Prakash K, Brown A, Roberts K, Paredes MF, Kawaguchi R, Stockley JH, Sabeur K, Chang SM, Huang E, Hutchinson P, Ullian EM, Hemberg M, Coppola G, Holt MG, Geschwind DH, Rowitch DH. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci. 2020 Mar 16. doi: 10.1038/s41593-020-0602-1.
[Epub ahead of print]

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.

Sunday, March 29, 2020

Raoult critique

Coronavirus COVID-19 pandemic is about to be stopped by a stroke of a French “genius” with a history of publishing manipulated data. The charismatic Didier Raoult, director of the Research Unit in Infectious and Tropical Emergent Diseases (URMITE) in Marseille has found a cure: the humble chloroquine, cheap unpatented substance used to treat malaria and autoimmune diseases lupus and rheumatism. The substance so far failed in all antiviral therapies, but this didn’t prevent Raoult from deciding that chloroquine can cure corona virus infections, serious side effects notwithstanding. To prove that, Raoult treated 26 patients at his institution with the derivative hydroxychloroquine, alone and in combination with the antibiotic (meaning antibacterial!) drug azithromycin. The study was not randomised, ethically approved only after it already began, and it was not really controlled: the 16 control patients were treated in different clinics.

After some adjustments (patients removed, data points guessed), a preprint was published simultaneously with a paper in a peer reviewed journal Raoult basically controls…

It is the opposite of proper clinical research practice. The trial started somewhere in March, likely before an ethics vote was applied for. But already on 11 February 2020 Raoult and colleagues decreed which drug can prevent and cure COVID-19…

As Elisabeth Bik discussed, the paper was peer-reviewed in less than 24h, it probably helped that the journal’s Editor-in-Chief is both the paper’s coauthor and Raoult’s IHU subordinate Jean-Marc Rolain. Bik also listed other problems with that paper. Like this:

“In the EU Clinical Trial Register page, the study was described as evaluating PCR data on Day 1, Day 4, Day 7 and Day 14. However, the study show the data for Day 6, which is different than planned. Why did the authors not show the results on Day 7? Did the data on day 7 not look as good?”…

In fact, the authors never showed the results of day 14 either. They also refused to share their secondary endpoint data, namely “the clinical effectiveness of treatment on time to apyrexia, normalization of respiratory rate, and average length of hospital stay and mortality”. Basically, it is none of anyone’s business to know if the therapy had any clinical benefit for the patients…

Even then, additional tricks were apparently needed. Viral load in control patients was analysed by quantitative RT-PCR and a bit too liberally, as Bik explains:

“Of particular note, control patients 6 and 8-16 appear to have been analyzed differently. Their Day 0 PCR values are not given as CT values (the number of cycles after which a PCR becomes positive, the lower the number, the more virus is present) but as POS/NEG, suggesting a different test was used. […] Several patients in the control group did not even have a PCR result on Day 6, so it is not clear how they were counted in the Day 6 result.”..

Some control patients were tested only every second day, afterwards guessed to be positive, some were not tested at all on day 0, as a PubPeer commented noted. And then the authors simply changed the results in control patients between the “in press” and the final paper version, as another PubPeer user observed…

Another PubPeer user re-ran the analysis, because “an important number of non-treated patients were not tested by PCR (ND)“. Once the ND values were disregarded, there wasn’t any more significant difference between controls and chloroquine-treated patients.

Not only control group had to be adjusted: the treatment group somehow lost 6 patients, as Bik discussed:

“Although the study started with 26 patients in the HQ or HQ+AZ group, data from only 20 treated patients are given, because not all patients completed the 6-day study. The data for these 20 patients looks incredibly nice; especially the patients who were given both medications all recovered very fast.

What happened to the other six treated patients? Why did they drop out of the study? Three of them were transferred to the intensive care unit (presumably because they got sicker) and 1 died. The other two patients were either too nauseous and stopped the medication, or left the hospital […] So 4 of the 26 treated patients were actually not recovering at all.”

It seems, the authors simply removed inconvenient patients from the analysis before publishing their study. They left online their previous evaluation though, which showed a slightly different result.
Statistical and ethical problems with that Gautret et al 2020 study were addressed extensively in this preprint by Dahly, Gates & Morris zenodo 2020. The authors also reject Raoult’s claims about previous positive results from China:

“In the background of their paper, Gautret et al referred to “an early clinical trial conducted in COVID-19 Chinese patients, [which] showed that chloroquine had a significant effect, both in terms of clinical outcome and viral clearance, when comparing to control groups”. There were two citations for this claim. The first was a letter7 that doesn’t report any trial data, but instead refers to a conference held in China in February, during which participants (“experts from government and regulatory authorities and organizers of clinical trials”) seemingly agreed that chloroquine was an efficacious treatment for COVID-19. The second cition (also included in the aforementioned letter) refers to a number of clinical trials registered in China, though many of these have now been suspended or closed, while the remaining trials are still recruiting (per their entries on http://www.chictr.org.cn as of March 21, 2020). Hence there are, to our knowledge, no other published reports of clinical trials testing the efficacy of chloroquine for COVID-19 treatment.”


I hear you ask that. After all, Raoult is a star of French science: he publishes a scientific paper “nearly every work day”, thanks to 800 employees working under him, as a blog post mentioned, and he is so important that he named two bacteria species after himself: Raoultella planticola and Rickettsia raoultii.

Well, Elisabeth Bik found some very bad data fakery in a 15 year old Raoult-co-authored paper…
Indeed, problems in a paper about a mouse model for typhus got his lab in hot water in 2006. A reviewer for Infection and Immunity, a journal published by the American Society for Microbiology (ASM), discovered that four figures in a revised manuscript were identical to figures in the original manuscript, even though they were supposed to describe a different experiment.

In letters to ASM, made available by Raoult, second author Christian Capo and last author Jean-Louis Mège, a group leader, accepted “full responsibility” for the problem, which they said involved only two figures. Capo, in his letter, wrote that he had made an innocent mistake; Mège wrote that Capo had subsequently failed to show the revised manuscript to other authors, who were on vacation, before resubmitting it. But after consulting its ethics panel, ASM banned all five authors, including Raoult, from publishing in its journals for a year. “We are not entirely comfortable with the explanation provided,” ASM officials wrote to Mège. “Misrepresentation of data … is an affront to the ethical conduct of scientific inquiry.”

Capo and Mège accepted the decision, but Raoult wrote ASM that he wasn’t at fault and that the “collective punishment” was “very unfair.” He appealed the ban, also on behalf of two other co-authors, but lost. Furious, he resigned from the editorial board of two other ASM journals, canceled his membership in the American Academy of Microbiology, ASM’s honorific leadership group, and banned his lab from submitting to ASM journals, in which he had published more than 230 studies. His name has been on only two ASM journal papers since, both published in 2010. To clear his name, Raoult sent his ASM correspondence to French colleagues in 2007, along with a letter defending himself. “If I had been in the United States, I would have sued,” he wrote.”…

Raoult did not like Science coverage of his genius. He made the journal publish an Erratum, where he even wrongly accused the author of shilling for Danone:

“IT WAS AN HONOR TO HAVE MY PROFILE PUBlished in Science (“Sound and fury in the microbiology lab,” C. Mary, News Focus, 2 March, p. 1033). However, I was surprised that 20% of the article is devoted to the American Society for Microbiology (ASM) story, in which I was a collateral victim of a collective sanction (there has been no collective liability in France since World War II). I did not manage the paper and did not even check the last version. The mistake by C. Capo consists of a single figure inversion (not four, as stated in the Science profile). This paper has since been published (1). In January 2007, I was awarded one of the highest ASM honors—the ICAAC lecture—thus clearing doubts about my scientific integrity.”

Now, the extra bit of irony is that Raoult is so full of himself that he published in 2018 an opinion piece to teach France some… research integrity…

Now consider this. Raoult’s past papers show falsified data, which even resulted in his ban by ASM for one year, to which Raoult responded with threats of lawsuit. He is a patriarchal control freak and a misogynous bully who violently punishes all disagreement and uses threats against whistleblowers and victims to achieve compliance. He is pathologically resistant to criticism and believes to be infallible and omniscient:.. Raoult’s new study on chloroquine as the cure for COVID19 is obviously flawed, at best.

Should we really trust his claims and put our all lives in his hands?

Thursday, March 26, 2020

Association of different thrombectomy techniques and devices with angiographic and clinical outcome parameters

Sporns PB, Straeter R, Minnerup J, Wiendl H, Hanning U, Chapot R, Henkes H, Henkes E, Grams A, Dorn F, Nikoubashman O, Wiesmann M, Bier G, Weber A, Broocks G, Fiehler J, Brehm A, Psychogios M, Kaiser D, Yilmaz U, Morotti A, Marik W, Nolz R, Jensen-Kondering U, Schmitz B, Schob S, Beuing O, Goetz F, Trenkler J, Turowski B, Möhlenbruch M, Wendl C, Schramm P, Musolino P, Lee S, Schlamann M, Radbruch A, Rübsamen N, Karch A, Heindel W, Wildgruber M, Kemmling A; Save ChildS Investigators. Does Device Selection Impact Recanalization Rate and Neurological Outcome?: An Analysis of the Save ChildS Study. Stroke. 2020 Apr;51(4):1182-
1189.  doi: 10.1161/STROKEAHA.119.028221. Epub 2020 Mar 2.

Background and Purpose- The recent Save ChildS study provides multicenter evidence for the use of mechanical thrombectomy in children with large vessel occlusion arterial ischemic stroke. However, device selection for thrombectomy may influence rates of recanalization, complications, and neurological outcomes, especially in pediatric patients of different ages. We, therefore, performed additional analyses of the Save ChildS data to investigate a possible association of different thrombectomy techniques and devices with angiographic and clinical outcome parameters. Methods- The Save ChildS cohort study (January 2000-December 2018) analyzed data from 27 European and United States stroke centers and included all pediatric patients (<18 years), diagnosed with arterial ischemic stroke who underwent endovascular recanalization. Patients were grouped into first-line contact aspiration (A Direct Aspiration First Pass Technique [ADAPT]) and non-ADAPT groups as well as different stent retriever size groups. Associations with baseline characteristics, recanalization rates (modified Treatment in Cerebral Infarction), complication rates, and neurological outcome parameters (Pediatric National Institutes of Health Stroke Scale after 24 hours and 7 days; modified Rankin Scale and Pediatric Stroke Outcome Measure at discharge, after 6 and 24 months) were investigated. Results- Seventy-three patients with a median age of 11.3 years were included. Currently available stent retrievers were used in 59 patients (80.8%), of which 4×20 mm (width×length) was the most frequently chosen size (36 patients =61%). A first-line ADAPT approach was used in 7 patients (9.6%), and 7 patients (9.6%) were treated with first-generation thrombectomy devices. In this study, a first-line ADAPT approach was neither associated with the rate of successful recanalization (ADAPT 85.7% versus 87.5% No ADAPT) nor with the complication rate or the neurological outcome. Moreover, there were no associations of stent retriever sizes with rates of recanalization, complication rates, or outcome parameters. Conclusions- Our study suggests that neurological outcomes are generally good regardless of any specific device selection and suggests that it is important to offer thrombectomy in eligible children regardless of technique or device selection. Registration- URL: https://www.drks.de/; Unique identifier: DRKS00016528.

Courtesy of:  https://www.mdlinx.com/journal-ummaries/stroke/2020/03/25/7629447?spec=neurology

Bell's palsy

Dear Care and Feeding,

About a month ago, as I was getting my 11-month-old ready for day care, I noticed that the left side of her face was drooping weirdly. My husband and I spent that evening consulting Google and more or less arrived at a diagnosis of Bell’s palsy. I made an appointment with her pediatrician.

The pediatrician, who has a stellar reputation, examined her for less than two minutes and announced he would have to immediately consult a pediatric neurologist. He left and returned about five minutes later, when he breathlessly said: “You need to go to the hospital right now. I’ve called ahead. They’re waiting for you at the emergency room.” I was stunned and asked what he thought it was. He answered, “Do you really want to know?” Without waiting for me to reply, he said, “Cranial nerve tumor.”

The next hour or so was a blur. We got to the ER, my husband left work, and he and I had to help the nurses restrain my baby while they stuck needles in her poor little hands and feet as she screamed in fear and pain. It was the worst day of my life. We sat through an MRI that evening and spent the night at the hospital and basically had to confront the possibility that our baby would die. And then, the next morning, we got the results: Bell’s palsy, probably caused by an ear or respiratory infection. It would clear up in a few months.

Our immediate relief has now given way to rage at the pediatrician who made us believe our daughter had a brain tumor based on a two-minute exam. Even the neurologist who delivered the MRI results told us, “No, a tumor wouldn’t even be in the first 10 things I’d check.” Every time I think of this incident, my blood boils. I want to write a letter to our now-ex-pediatrician and explain that this was a traumatic, devastating, and totally unnecessary and irresponsible thing for him to do. I want to publicly ream him out for this and make sure he cannot ever put another parent through what we went through that day. I know doctors aren’t perfect, but this seems inexcusable, and a big part of me wants some kind of justice. Please give me some perspective.

Dear Traumatized,

I’m sorry for this ordeal. It sounds awful.

But please consider that there are parents and children subjected to the same—indeed worse—who don’t get the happy reprieve of a non-life-threatening diagnosis. There are parents who have to restrain their infants for medical procedures day after day, and they would love the relief you are now able to enjoy.

You’re mad at your doctor, and mad on behalf of your kid being put through all that unnecessary pain, and maybe mad at the world, generally, that it contains this kind of fear and stress. It’s maddening. I understand.

I cannot say whether your doctor was negligent or impulsive or anything else; you can’t either, though the clarity of hindsight makes you believe you can. Honestly, it doesn’t matter. You have a healthy baby. You don’t need justice too. Let this go.

Sunday, March 22, 2020

Use of perampanel and a ketogenic diet in nonketotic hyperglycinemia

Daida A, Hamano SI, Ikemoto S, Hirata Y, Matsuura R, Koichihara R, Oba D, Ohashi H. Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report. Neuropediatrics. 2020 Mar 16. doi: 10.1055/s-0040-1708536. [Epub ahead of print]

 Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor.

 The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid.

 Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

Epilepsy and cannabidiol: a guide to treatment

Arzimanoglou A, Brandl U, Cross JH, Gil-Nagel A, Lagae L, Landmark CJ, Specchio N, Nabbout R, Thiele EA, Gubbay O, The Cannabinoids International Experts Panel; Collaborators. Epilepsy and cannabidiol: a guide to treatment. Epileptic Disord. 2020 Feb 1;22(1):1-14. doi: 10.1684/epd.2020.1141.

The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.

Fenfluramine and stiripentol for Dravet syndrome

Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial. JAMA Neurol. 2020;77(3):300–308. doi:10.1001/jamaneurol.2019.4113

Key Points
Question  Is fenfluramine safe and effective for treating patients with Dravet syndrome who have frequent seizures despite taking a stiripentol-inclusive antiepileptic drug regimen?

Findings  Oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) provided a 54.0% greater reduction in mean monthly convulsive seizure frequency than placebo in patients with Dravet syndrome who were taking stiripentol-containing antiepileptic drug regimens; a significantly greater proportion of patients who were taking fenfluramine (vs placebo) experienced a clinically meaningful (≥50%) or profound (≥75%) reduction in monthly convulsive seizure frequency. The most common adverse events included decreased appetite, pyrexia, fatigue, and diarrhea; no patient developed valvular heart disease or pulmonary hypertension.

Meaning  Adjunctive fenfluramine may be a safe, effective new treatment option for patients with Dravet syndrome with seizures that are not controlled by a regimen including stiripentol.

Importance  Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens.

Objective  To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens.

Design, Setting, and Participants  This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens.

Interventions  Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary.

Main Outcomes and Measures  The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline.

Results  A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.

Conclusions and Relevance  Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome.

Trial Registration  ClinicalTrials.gov identifier: NCT02926898

Courtesy of:  https://www.mdlinx.com/journal-summaries/seizure-disorders-dravet-syndrome-treatments-prevention/2020/03/12/7527294?spec=neurology

Thursday, March 19, 2020

Hydroxychloroquine and azithromycin as a treatment of COVID-19

Philippe Gautret, Jean-Christophe Lagier,  Philippe Parola,  Van Thuan Hoang, Line Meddeb, Morgane Mailhe,, Barbara Doudier,, Johan Courjone, Valérie Giordanengoh, Vera Esteves Vieira, Hervé Tissot Dupont,  Stéphane Honoréi, Philippe Colson,  Eric Chabrière, Bernard La Scola,  Jean-Marc Rolain, Philippe Brouqui, Didier Raoult.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial


Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and
reported to be efficient in Chinese COV-19 patients. We evaluate the role of
hydroxychloroquine on respiratory viral loads.

Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early
March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in
nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical
presentation, azithromycin was added to the treatment. Untreated patients from another center
and cases refusing the protocol were included as negative controls. Presence and absence of
virus at Day6-post inclusion was considered the end point.

Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight
had lower respiratory tract infection symptoms. 
Twenty cases were treated in this study and showed a significant reduction of the viral
carriage at D6-post inclusion compared to controls, and much lower average carrying duration
than reported of untreated patients in the literature. Azithromycin added to
hydroxychloroquine was significantly more efficient for virus elimination.

Despite its small sample size our survey shows that hydroxychloroquine treatment is
significantly associated with viral load reduction/disappearance in COVID-19 patients and its
effect is reinforced by azithromycin.


Wednesday, March 18, 2020

Visual snow and migraine

Hodak J, Fischer U, Bassetti CLA, Schankin CJ. Episodic Visual Snow Associated With Migraine Attacks. JAMA Neurol. 2019 Nov 25. doi:10.1001/jamaneurol.2019.4050. [Epub ahead of print]

Visual snow syndrome (VSS) is a debilitating disorder characterized by continuous visual snow (VS), ie, tiny flickering dots in the entire visual field resembling the view of a badly tuned analog television, plus additional visual symptoms, such as photophobia and palinopsia. There is a high comorbidity with migraine and migraine aura. To our knowledge, this is the first report of patients with an episodic form of VS (eVS), strictly co-occurring with migraine attacks.

Between January 2016 and December 2017, we saw 3 patients with eVS and 1934 patients with migraine at our tertiary outpatient headache center. Diagnoses were made according to the International Headache Society International Classification of Headache Disorders-32 and our previous work, except for the requirement of permanence for VS. The case series was approved by the Cantonal Ethics Committee Bern (Req-2017-00698) with waiver of written informed consent based on general consent given by all patients.

The 3 patients presented initially for headache as chief complaint. They denied VS outside migraine attacks and did not report additional visual symptoms suggestive of VSS during headache except for photophobia. Neurological examination and magnetic resonance imaging results were normal.

Patients experienced black and white (2 patients) or black and yellow (1 patient) eVS during migraine attacks, nonfluctuating in distribution and severity. Episodes lasted from less than 2 minutes before and during the attack in 1 patient to during the entire migraine attack in 2 patients.

Three patients report episodes of VS exclusively at the beginning or during migraine attacks. The description was identical and matched the definition of VS in VSS except for not being continuous. In the syndrome-defining study, only patients with continuous VS were included, impeding the identification of an episodic form. Based on the present case series, we propose to distinguish between VSS, a debilitating disorder characterized by continuous VS and additional visual symptoms persisting over years, and eVS, an uncommon self-limiting symptom during migraine attacks.

The relationship between migraine and VSS is still unresolved. Although the severity of VS in VSS does not fluctuate in parallel to the migraine cycle, the strict co-occurrence of eVS and migraine reported here epitomizes a close proximity. This is in agreement with the clinical picture of migraine being a disorder of sensory processing and VSS being a disorder of visual processing and also with neuroimaging showing overlapping dysfunctional areas in the visual association cortex.

Episodic VS is uncommon given that only 3 of 1934 patients with migraine (<0.2%) were identified despite asking routinely for visual symptoms. It was remarkably linked to migraine attacks and occurred without the additional symptoms found in VSS.  In the first patient, the occurrence prior to headache attacks might suggest an aura phenomenon. However, the history of migraine without aura in all patients, the brief duration in 1 patient and long duration in 2 patients, the affection of the entire visual field, and the lack of directed movement speak against a cortical spreading depressionlike mechanism6 and thus against eVS being an aura symptom. In clinical practice, a detailed history in patients reporting visual flickering is therefore necessary to differentiate aura from eVS. This is important because the diagnosis of aura might have implications for patient guidance on contraception or timing of triptan intake.

Sunday, March 15, 2020

Predicting autism/intellectual disability in infants with West syndrome

Ouss L, Palestra G, Saint-Georges C, Leitgel Gille M, Afshar M, Pellerin H, Bailly K, Chetouani M, Robel L, Golse B, Nabbout R, Desguerre I, Guergova-Kuras M, Cohen D. Behavior and interaction imaging at 9 months of age predict autism/intellectual disability in high-risk infants with West syndrome. Transl Psychiatry. 2020 Feb 3;10(1):54.

Automated behavior analysis are promising tools to overcome current assessment limitations in psychiatry. At 9 months of age, we recorded 32 infants with West syndrome (WS) and 19 typically developing (TD) controls during a standardized mother-infant interaction. We computed infant hand movements (HM), speech turn taking of both partners (vocalization, pause, silences, overlap) and motherese. Then, we assessed whether multimodal social signals and interactional synchrony at 9 months could predict outcomes (autism spectrum disorder (ASD) and intellectual disability (ID)) of infants with WS at 4 years. At follow-up, 10 infants developed ASD/ID (WS+). The best machine learning reached 76.47% accuracy classifying WS vs. TD and 81.25% accuracy classifying WS+ vs. WS-. The 10 best features to distinguish WS+ and WS- included a combination of infant vocalizations and HM features combined with synchrony vocalization features. These data indicate that behavioral and interaction imaging was able to predict ASD/ID in high-risk children with WS.

Whole-brain resting-state functional connections assisting the diagnosis of ADHD

Sun Y, Zhao L, Lan Z, Jia XZ, Xue SW. Differentiating Boys with ADHD from Those with Typical Development Based on Whole-Brain Functional Connections Using a Machine Learning Approach. Neuropsychiatr Dis Treat. 2020;16:691-702 https://doi.org/10.2147/NDT.S239013


Purpose: In recent years, machine learning techniques have received increasing attention as a promising approach to differentiating patients from healthy subjects. Therefore, some resting-state functional magnetic resonance neuroimaging (R-fMRI) studies have used interregional functional connections as discriminative features. The aim of this study was to investigate ADHD-related spatially distributed discriminative features derived from whole-brain resting-state functional connectivity patterns using machine learning.

Patients and Methods: We measured the interregional functional connections of the R-fMRI data from 40 ADHD patients and 28 matched typically developing controls. Machine learning was used to discriminate ADHD patients from controls. Classification performance was assessed by permutation tests.

Results: The results from the model with the highest classification accuracy showed that 85.3% of participants were correctly identified using leave-one-out cross-validation (LOOV) with support vector machine (SVM). The majority of the most discriminative functional connections were located within or between the cerebellum, default mode network (DMN) and frontoparietal regions. Approximately half of the most discriminative connections were associated with the cerebellum. The cerebellum, right superior orbitofrontal cortex, left olfactory cortex, left gyrus rectus, right superior temporal pole, right calcarine gyrus and bilateral inferior occipital cortex showed the highest discriminative power in classification. Regarding the brain–behaviour relationships, some functional connections between the cerebellum and DMN regions were significantly correlated with behavioural symptoms in ADHD (P < 0.05).

Conclusion: This study indicated that whole-brain resting-state functional connections might provide potential neuroimaging-based information for clinically assisting the diagnosis of ADHD.

Courtesy of:  https://www.mdlinx.com/journal-summaries/attention-deficit-hyperactivity-disorder-adhd-magnetic/2020/03/13/7526845?spec=neurology

Friday, March 13, 2020

THOC2 mutations

Inspired by a patient

Kumar R, Gardner A, Homan CC, Douglas E, Mefford H, Wieczorek D, Lüdecke HJ, Stark Z, Sadedin S; Broad CMG, Nowak CB, Douglas J, Parsons G, Mark P, Loidi L, Herman GE, Mihalic Mosher T, Gillespie MK, Brady L, Tarnopolsky M, Madrigal I, Eiris J, Domènech Salgado L, Rabionet R, Strom TM, Ishihara N, Inagaki H, Kurahashi H, Dudding-Byth T, Palmer EE, Field M, Gecz J. Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery. Hum Mutat. 2018 Aug;39(8):1126-1138.

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.

Kumar R, Corbett MA, van Bon BW, Woenig JA, Weir L, Douglas E, Friend KL, Gardner A, Shaw M, Jolly LA, Tan C, Hunter MF, Hackett A, Field M, Palmer EE, Leffler M, Rogers C, Boyle J, Bienek M, Jensen C, Van Buggenhout G, Van Esch H, Hoffmann K, Raynaud M, Zhao H, Reed R, Hu H, Haas SA, Haan E, Kalscheuer VM, Gecz J. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability. Am J Hum Genet. 2015 Aug 6;97(2):302-10.

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

Di Gregorio E, Bianchi FT, Schiavi A, Chiotto AM, Rolando M, Verdun di Cantogno L, Grosso E, Cavalieri S, Calcia A, Lacerenza D, Zuffardi O, Retta SF, Stevanin G, Marelli C, Durr A, Forlani S, Chelly J, Montarolo F, Tempia F, Beggs HE, Reed R, Squadrone S, Abete MC, Brussino A, Ventura N, Di Cunto F, Brusco A.  A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar
hypoplasia. J Med Genet. 2013 Aug;50(8):543-51.

We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia.

Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C.elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels.

We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia.

Thursday, March 12, 2020

Initial treatment with newer versus injectable disease-modifying therapies In pediatric multiple sclerosis

P066 - Real-world Effectiveness Of Initial Treatment With Newer Versus Injectable Disease-modifying Therapies In Pediatric Multiple Sclerosis
Author Block: K. M. Krysko1, J. S. Graves2, M. Rensel3, B. Weinstock-Guttman4, A. Rutatangwa1, G. Aaen5, B. Anita6, L. Benson7, T. Chitnis8, M. Gorman7, M. S. Goyal9, Y. Harris10, L. Krupp6, T. Lotze11, S. Mar12, M. Moodley3, J. Ness13, M. Rodriguez14, J. Rose15, T. Schreiner16, J. Tillema14, M. Waltz17, T. Casper17, E. Waubant1; 1Department of Neurology, University of California San Francisco, San Francisco, CA, 2Department of Neurology, University of California San Diego, La Jolla, CA, 3Department of Neurology, Cleveland Clinic, Cleveland, OH, 4Department of Neurology, State University of New York at Buffalo, Buffalo, NY, 5Department of Pediatrics, Loma Linda University, San Bernardino, CA, 6Department of Neurology, New York University Langone Medical Center, New York, NY, 7Department of Neurology, Boston Children’s Hospital, Boston, MA, 8Department of Pediatric Neurology, Massachusetts General Hospital, Boston, MA, 9Mallinckrodt Institute of Radiology, Washington University in Saint Louis, St. Louis, MO, 10Department of Nursing, University of Alabama at Birmingham, Birmingham, AL, 11Department of Neurology, Texas Children’s Hospital, Houston, TX, 12Department of Neurology, Washington University in Saint Louis, St. Louis, MO, 13Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, 14Department of Neurology, Mayo Clinic, Rochester, MN, 15Department of Neurology, University of Utah, Salt Lake City, UT, 16Departments of Neurology & Pediatrics, University of Colorado, Aurora, CO, 17Department of Pediatrics, University of Utah, Salt Lake City, UT.

Background: Treatment of pediatric multiple sclerosis (MS) is challenging as most disease-modifying therapies (DMT) lack randomized controlled trial data in children.

Objectives: We assessed real-world effectiveness of initial treatment with newer compared to injectable DMTs on disease activity in pediatric MS and clinically isolated syndrome (CIS).

Methods: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-beta or glatiramer acetate) DMTs. Propensity scores (PS) were computed with logistic regression to predict newer DMT use, including pre-identified confounders (sex, race, ethnicity, site, age at onset and first DMT, first event characteristics, height, weight, diagnosis, number of relapses in prior 6 months, new T2 hyperintense or gadolinium enhancing lesions in prior 6 months, baseline EDSS). Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2 hyperintense and gadolinium-enhancing lesions on MRI brain were modeled with midpoint survival analyses, adjusted for PS-quintile.

Results: 741 children (66% female, 15% CIS) began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs. injectable 14.4 years, p=0.001) and less likely to have a monofocal presentation (37% vs. injectable 55%, p<0.001). Number of relapses in the prior 6 months was slightly lower in those started on newer DMT (0.8 vs. injectable 1.0), while first event severity and EDSS were similar between groups. Balance in confounders was acceptable within PS-quintiles. In PS-quintile adjusted analysis, those started on newer DMTs had lower relapse rate than those on injectables (rate ratio 0.45, 95% CI 0.29-0.70, p<0.001; rate difference 0.27, 95% CI 0.14-0.40, p=0.004). One would need to treat with newer over injectable DMTs for 3.7 person-years to prevent one relapse. Those started on newer DMTs also had lower rate of new/enlarging T2 (HR 0.51, 95% CI 0.36-0.72, p<0.001) and gadolinium-enhancing lesions (HR 0.38, 95% CI 0.23-0.63, p<0.001) than those on injectables.

Conclusions: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs is required.

Courtesy of:  https://www.neurologyadvisor.com/conference-highlights/actrims-forum-2020/new-pediatric-multiple-sclerosis-therapies-more-effective-than-injectables/

Monday, March 9, 2020

CRISPR editing for sickle cell disease

Gray had been exploring the possibility of getting a bone marrow transplant when Frangoul told her about a plan to study gene editing with CRISPR to try to treat sickle cell for the first time. She jumped at the chance to volunteer.

"I was excited," Gray says.

CRISPR enables scientists to edit genes much more easily than ever before. Doctors hope it will give them a powerful new way to fight cancer, AIDS, heart disease and a long list of genetic afflictions.

"CRISPR technology has a lot of potential use in the future," Frangoul says.

To try to treat Gray's sickle cell, doctors started by removing bone marrow cells from her blood last spring.

Next, scientists used CRISPR to edit a gene in the cells to turn on the production of fetal hemoglobin. It's a protein that fetuses make in the womb to get oxygen from their mothers' blood.

"Once a baby is born, a switch will flip on. It's a gene that tells the ... bone marrow cells that produce red cells to stop making fetal hemoglobin," says Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare's TriStar Centennial Medical Center.

The hope is that restoring production of fetal hemoglobin will compensate for the defective adult-hemoglobin sickle cells that patients produce.

"We are trying to introduce enough ... fetal hemoglobin into the red blood cell to make the red blood cell go back to being happy and squishy and not sticky and hard, so it can go deliver oxygen where it's supposed to," Frangoul says.

Then on July 2, after extracting Gray's cells and sending them to a lab to get edited, Frangoul infused more than 2 billion of the edited cells into her body.

"They had the cells in a big syringe. And when it went in, my heart rate shot up real high. And it kind of made it hard to breath," Gray says. "So that was a little scary, tough moment for me."

After that moment passed, Gray says, she cried. But her tears were "happy tears," she adds…
Other doctors and scientists are excited about the research. But they're cautious too.

"This is an exciting moment in medicine," says Laurie Zoloth, a bioethicist at the University of Chicago. "Everyone agrees with that. CRISPR promises the capacity to alter the human genome and to begin to directly address genetic diseases."

Still, Zoloth worries that the latest wave of genetic studies, including the CRISPR sickle cell study, may not have gotten enough scrutiny by objective experts.

"This a brand-new technology. It seems to work really well in animals and really well in culture dishes," she says. "It's completely unknown how it works in actual human beings. So there are a lot of unknowns. It might make you sicker."

Zoloth is especially concerned because the research involves African Americans, who have been mistreated in past medical studies.

Frangoul acknowledges that there are risks with experimental treatments. But he says the research is going very slowly with close oversight by the Food and Drug Administration and others…

About two months later, Gray has recovered enough to leave the hospital. She has been living in a nearby apartment for several weeks.

Enough time has passed since Gray received the cells for any concerns about immediate side effects from the cells to have largely passed. And her gene-edited cells have started working well enough for her immune system to have resumed functioning.

So Gray is packing. She will finally go home to see her children in Mississippi for the first time in months. Gray's husband is there to drive her home.

"I'm excited," she says. "I know it's going to be emotional for me. I miss the hugs and the kisses and just everything."…

"So look at this," says Frangoul, smiling, as he hands her a sheet of paper. "This is very exciting. I am super-excited about your results today."

Gray's CRISPR-edited cells seem to be working.

"It looks like there are signs that you are starting to make fetal hemoglobin, which is very exciting for us," Frangoul says.

Nearly half the hemoglobin in Gray's blood is now fetal hemoglobin, which is more than doctors think is needed to help alleviate the complications of sickle cell. And the level of that protein seems to be continuing to rise.

"Oh my goodness," Gray says.

The treatment also still seems safe, so far. There have been no signs of any ill effects from the modified cells.

In addition, there are clues that the cells could already be helping Gray. She hasn't needed any blood transfusions since she got the cells, hasn't had any pain attacks and hasn't had to rush to the hospital for help.

"That's good. Excellent. Perfect," Frangoul says. "This is extremely encouraging."

Typically, Gray says, she would have had another pain episode by now.

"I would have had at least had something," she says.

"It's special, especially coming up on the holidays — because sometimes I would be in the hospital on Christmas," Gray says. "So I'm looking forward to a whole new life for all of us."…

Zoloth, the University of Chicago bioethicist, says she's encouraged to see progress for a disease that has long been neglected. But she's still cautious about the research, especially because only one patient has been treated, and so recently. She worries about raising false hope.

"So far so good," Zoloth says. "And of course that's great news. I hope it works. I hope she's free of this disease, and I hope this very, very brave woman has a life of joy and freedom from pain and can raise those beautiful children."

But, she adds, "it's still very early days. We're still waiting for real news — which is, 'This is the definitive cure. This will help many, many thousands of people.' It would be a wonderful thing for humanity."

Other doctors are using CRISPR to try to treat cancer. One team soon plans to try to edit genes inside the body for the first time — modifying genes in retinal cells of the eye to try to restore vision to people blinded by a rare genetic disorder.

Gray knows this is just the beginning. But she's happy things are going well so far.

"It's amazing to have a chance at a different type of life," Gray says. "It's a miracle. When you pray and ask God for something for so long, all you have left is hope."

Gray has already started doing things she could never do before, such as go to one of her son's football games for the first time.

"I don't really want anything extravagant," she says. "I just want a simple life with my family and the people who I love and people that love me — and just live, you know?" Gray says. "This could be the beginning of something special."


See: https://childnervoussystem.blogspot.com/2019/07/doctors-in-us-use-crispr-tool-to-treat.html

CRISPR editing for Leber congenital amaurosis

Scientists say they have used the gene editing tool CRISPR inside someone's body for the first time, a new frontier for efforts to operate on DNA, the chemical code of life, to treat diseases.

A patient recently had it done at the Casey Eye Institute at Oregon Health & Science University in Portland for an inherited form of blindness, the companies that make the treatment announced Wednesday. They would not give details on the patient or when the surgery occurred.

It may take up to a month to see if it worked to restore vision. If the first few attempts seem safe, doctors plan to test it on 18 children and adults.

“We literally have the potential to take people who are essentially blind and make them see,” said Charles Albright, chief scientific officer at Editas Medicine, the Cambridge, Massachusetts-based company developing the treatment with Dublin-based Allergan. “We think it could open up a whole new set of medicines to go in and change your DNA.”

Dr. Jason Comander, an eye surgeon at Massachusetts Eye and Ear in Boston, another hospital that plans to enroll patients in the study, said it marks “a new era in medicine” using a technology that “makes editing DNA much easier and much more effective.”

Doctors first tried in-the-body gene editing in 2017 for a different inherited disease using a tool called zinc fingers. Many scientists believe CRISPR is a much easier tool for locating and cutting DNA at a specific spot, so interest in the new research is very high.

The people in this study have Leber congenital amaurosis, caused by a gene mutation that keeps the body from making a protein needed to convert light into signals to the brain, which enables sight. They're often born with little vision and can lose even that within a few years.

Scientists can't treat it with standard gene therapy -- supplying a replacement gene -- because the one needed is too big to fit inside the disabled viruses that are used to ferry it into cells.

So they're aiming to edit, or delete the mutation by making two cuts on either side of it. The hope is that the ends of DNA will reconnect and allow the gene to work as it should.
t's done in an hour-long surgery under general anesthesia. Through a tube the width of a hair, doctors drip three drops of fluid containing the gene editing machinery just beneath the retina, the lining at the back of the eye that contains the light-sensing cells.

"Once the cell is edited, it’s permanent and that cell will persist hopefully for the life of the patient," because these cells don't divide, said one study leader not involved in this first case, Dr. Eric Pierce at Massachusetts Eye and Ear.

Doctors think they need to fix one tenth to one third of the cells to restore vision. In animal tests, scientists were able to correct half of the cells with the treatment, Albright said.

The eye surgery itself poses little risk, doctors say. Infections and bleeding are relatively rare complications.

One of the biggest potential risks from gene editing is that CRISPR could make unintended changes in other genes, but the companies have done a lot to minimize that and to ensure that the treatment cuts only where it's intended to, Pierce said. He has consulted for Editas and helped test a gene therapy, Luxturna, that's sold for a different type of inherited blindness.

Some independent experts were optimistic about the new study.

“The gene editing approach is really exciting. We need technology that will be able to deal with problems like these large genes,” said Dr. Jean Bennett, a University of Pennsylvania researcher who helped test Luxturna at the Children’s Hospital of Philadelphia.

In one day, she had three calls from families seeking solutions to inherited blindness.

“It’s a terrible disease," she said. "Right now they have nothing.”


Sunday, March 8, 2020

Medical mayhem 15

A plastic surgeon primarily based in Ohio was arrested Friday by the FBI for allegedly drugging multiple women to the point of unconsciousness and raping them on camera.

Dr. Manish Gupta, 49, is charged with illegally dispensing controlled substances, aggravated sexual abuse and sex trafficking, Toledo's WTVG reported. He was booked into Lucas County Corrections Center in Toledo Friday afternoon after a federal search warrant on his phone, residence, personal vehicle and two offices in Lucas County uncovered sex toys, camera equipment, SD cards and vials of Diazepam and Ketamine, which are controlled substances not used in his medical practice, according to WTVG.

While visiting Los Angeles in 2016 to attend a plastic surgery convention, Gupta allegedly arranged for sex with a high-end escort, drugged her to the point of unconsciousness and raped her, according to a court filing in the U.S. District Court in Toledo.

The woman did not file a police report at the time. She took an at-home drug test that showed she had signs of benzodiazepine, a type of medication known as a tranquilizer, in her system, Toledo's WTOL reported, citing the court filing. She later visited the Rape Treatment Center at the UCLA Medical Center, Santa Monica, where she had a rape kit exam performed, WTVG reported.

The woman researched Gupta in an online database used by sex workers to make others aware of possibly dangerous individuals, according to the filing. She said she found multiple other women had reported a man either matching Gupta’s name or description, claiming he drugged, raped and possibly recorded them without their consent, WTOL reported.

Gupta is a board-certified plastic surgeon and medical doctor licensed in both Ohio and Michigan. He owns Artisan Cosmetic Surgery, which has two offices in Ohio and one in Michigan, WTVG reported.

The FBI launched an investigation into the claims against Gupta in January 2019. The investigation revealed that in 2014, an employee working for Gupta found multiple SDs with videos showing the plastic surgeon performing sex acts on motionless women who appeared to be unconscious. In February of this year, the State of Ohio Medical Board received a complaint claiming Gupta had been drugging and raping women for years.


Friday, March 6, 2020

Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy

Madsen KL, Buch AE, Cohen BH, Falk MJ, Goldsberry A, Goldstein A, Karaa A, Koenig MK, Muraresku CC, Meyer C, O'Grady M, Scaglia F, Shieh PB, Vockley J, Zolkipli-Cunningham Z, Haller RG, Vissing J. Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial. Neurology. 2020 Feb 18;94(7):e687-e698. doi: 10.1212/WNL.0000000000008861.

To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.

In cohorts of 8-13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).

No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.

Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.


This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.

Neonatal developmental and epileptic encephalopathies

El Kosseifi C, Cornet MC, Cilio MR. Neonatal Developmental and Epileptic Encephalopathies. Semin Pediatr Neurol. 2019 Dec;32:100770. doi:10.1016/j.spen.2019.08.006.

The new concept of developmental and epileptic encephalopathy is based on the understanding that many genetic epilepsies are associated with developmental impairment as a direct consequence of the genetic mutation, in addition to the effect of the frequent epileptic activity on brain development. As an example, in infants with KCNQ2 or STXBP1 encephalopathy, seizures may be controlled early after onset or cease spontaneously after a few years, but the developmental consequences tend to remain profound. The term "developmental and epileptic encephalopathy" expresses the concept that the genetic defect may be responsible for both the epilepsy and adverse development which is crucial to understanding the disease process for both families and clinicians. The increased use of EEG monitoring, neuroimaging, and metabolic and genetic testing in the Neonatal Intensive Care Unit has greatly improved our understanding of neonatal-onset epilepsies as seen with the syndromes Ohtahara and Early Myoclonic Encephalopathy outlined in the 1970s into distinct etiology-specific electroclinical phenotypes.

Treatable and novel genetic causes of Leigh syndrome

Lee JS, Yoo T, Lee M, Lee Y, Jeon E, Kim SY, Lim BC, Kim KJ, Choi M, Chae JH.Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. Clin Genet. 2020 Feb 5. doi: 10.1111/cge.13713. [Epub ahead of print] 

Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole-exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin-thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.

Tuesday, March 3, 2020

Long QT syndrome

An 18-year-old woman presents to the emergency department (ED) after experiencing a syncopal episode while backpacking two days ago. The patient states that she had been hiking with her friends up a steep hill, and the next thing that she remembered was waking up, lying on the trail. The event was not witnessed by any of her friends, and the patient does not recall any antecedent chest pain, shortness of breath, palpitations, or dizziness. She denies biting her tongue or having incontinence at the time of the event, but she remembers feeling briefly dazed. This feeling resolved quickly without any intervention. After a period of rest, she was able to finish the hike without further problems.

Just to be safe, she has come to the ED to get checked out because she could not get an appointment to see her primary care provider. She denies any past medical problems, but she does report experiencing a similar syncopal episode a few years ago that also occurred while she had been exerting herself. At that time, she had dismissed the episode as nothing important because she had skipped breakfast that morning. The patient also recalls that her younger brother has had similar episodes of syncope over the past few years.

She has no recent history of illness or fever and does not report any chest pains, shortness of breath, or palpitations subsequent to the event. She also denies any recent dieting or use of any over-the-counter or illicit drugs. Her menses have been normal and she takes a multivitamin every day. She is not currently taking any medications and denies having any allergies. She is a high school senior and lives at home in a safe environment with her family. She is looking forward to starting college in the fall. She denies knowledge of any cardiac or neurologic problems in her family...

[Examination was unremarkable.  Among other studies, an EKG was obtained.] 

The ECG demonstrates prolongation of the QT segment as demonstrated by a QT interval of 0.6 seconds, with a calculated QTc of 0.61 seconds

The diagnosis of [long QT syndrome] LQTS has been increasingly recognized as a cause of unexplained dizziness, syncope, and sudden cardiac death in otherwise healthy, young individuals. The prevalence is difficult to estimate, but rough estimates place the occurrence at 1 in 10,000 individuals. This number is difficult to ascertain because 10%-15% of patients with LQTS genetic defects have a normal QTc duration at various times  Most patients with congenital forms of the disease develop symptoms in childhood or adolescence. The age of first presentation is somewhat dependent on the specific genotype inherited. The possibility of this diagnosis should be considered in any patient with a history similar to the one in this case.

Congenital LQTS is now considered to be a heritable abnormality in one of the cardiac myocyte membrane sodium and potassium channels. Several specific genotypes have been identified, with different mutations. Twelve different types of LQTS have been identified, with types 1, 2, and 3 accounting for most cases (45%, 45%, and 7%, respectively). In both LQT1 and LQT2, the potassium ion current is affected. However, in LQT3, the sodium ion current is affected. Other notable elements of the most common forms are include the following:

LQT1: Swimming or strenuous exercise can trigger malignant arrhythmias in this type.

LQT2: Sudden emotional stress can trigger arrhythmias in this type. Postpartum women with LQT2 are susceptible.

LQT3: Malignant arrhythmias occur during rest.

The QT interval reflects the duration of activation and recovery of the ventricular myocardium. Prolonged recovery from electrical excitation raises the chance for dispersing refractoriness, when some parts of myocardium may be refractory to depolarization. From a physiologic standpoint, dispersion occurs with repolarization between three layers of the heart. Also, the repolarization phase is often prolonged in the mid-myocardium. Thus, the T wave is normally wide; the interval from Tpeak to Tend (Tp-e) indicates the transmural dispersion of repolarization (TDR). In LQTS, TDR increases and creates a functional substrate for transmural reentry.

In LQTS, mutations lead to a prolonged QT segment resulting from prolongation of cardiomyocyte repolarization, with the potential for degeneration to a specific type of polymorphic ventricular tachycardia known as torsade de pointes (translated as "twisting of the points"). These episodes of torsades de pointes are more likely to occur with increased catecholamine levels (adrenergic dependent or tachycardia dependent). Torsade de pointes is characterized by a ventricular rate greater than 200 bpm, in which the QRS structure has an undulating axis that shifts polarity about the baseline. This rhythm can spontaneously convert to a sinus rhythm or degenerate into ventricular fibrillation. Depending on the duration of arrhythmic activity and concomitant comorbidities, patients may experience dizziness, seizures, syncope, or sudden death. Episodes are usually extremely brief and resolve spontaneously, but they have a tendency to recur in rapid succession, leading to more serious complications.

A related important point to assess in patients with a familial history of unexplained syncope or sudden death is an associated history of hearing loss. Some forms of LQTS (eg, Jervell and Lange-Nielsen syndrome) are accompanied by congenital neuronal deafness. Other forms (eg, Romano-Ward syndrome) do not have an associated hearing loss. Formal diagnosis of congenital LQTS is usually established on the basis of the clinical presentation, the ECG findings, and the family history. Genetic testing for specific deficits is not currently the standard of care.

In addition to the congenital forms, acquired forms of LQTS are commonly encountered in the ED. Acquired QT prolongation is usually induced by medication. Acquired forms are often the result of drug therapy with various antiarrhythmic medications (primarily those of class IA and class III), phenothiazines, cyclic depressants, antihistamines, and some antimicrobials (quinolones). Resultant torsade de pointes is usually observed within one to two weeks of the start of the QT-altering medication; however, delayed presentations can also occur if a combination of medications that affect the QT interval are added to the patient's regimen.

Other causes of prolongation of the QT interval include electrolyte disturbances (hypokalemia, hypomagnesemia, and, in rare cases, hypocalcemia), myocardial ischemia, autonomic neuropathy, hypothyroidism, use of drugs (eg, cocaine, amphetamines), and cerebrovascular accidents (intraparenchymal or subarachnoid hemorrhage).

Treatment of patients with LQTS can be divided into short-term and long-term strategies.  Short-term strategies include immediate management of unstable rhythms (torsade de pointes), regardless of the specific etiology of the QT prolongation. Immediate treatment with magnesium sulfate is the agent of choice for all forms of LQTS. This is frequently accompanied by potassium chloride, even in patients for whom the serum potassium level is only in the lower range of normal. In acquired LQTS, withdrawal of the offending agent and/or electrolyte repletion is often all that is necessary to prevent recurrences in most patients. The exception is in patients with sick sinus syndrome or atrioventricular blocks in which a pause or bradycardia precipitates torsades de pointes. These patients require permanent pacemakers. In contrast, all patients with congenital LQTS require long-term treatment.

The cornerstone of therapy is life-long adrenergic blockade with beta-blockers, which reduces the risk for arrhythmia. In some patients, beta-blockers may also shorten the QT interval. Propranolol and nadolol are the two most commonly prescribed beta-blockers. These patients should also avoid any drugs that are known to prolong the QT interval or those that reduce serum potassium or magnesium levels. Advice is mixed regarding whether all asymptomatic patients should be treated with beta-blockers, or just those at high risk for an acute cardiac event.

In cases refractory to adrenergic blockade, several additional, more aggressive measures are also available. Left thoracic sympathectomy may be used in conjunction with beta-blockers to provide increased adrenergic blockade. The permanent implantation of a pacemaker or cardiac defibrillator has been effective in reducing the incidence of sudden cardiac death in high-risk patients. In certain subtypes of LQTS, patients are advised to avoid strenuous activity, in particular swimming or diving.

At this time, there are no established gene-specific therapies widely in use, although several treatment modalities are under investigation in both limited human trials and animal models. All family members of those patients with suspected LQTS are encouraged to be screened by an ECG, but not by genetic testing. Genetic testing is not extensive enough to cover all potential mutations at this time, and it is reserved mainly as a research tool.

The patient in this case was admitted to a cardiac telemetry unit after a discussion with the on-call cardiologist for further evaluation and management. On the basis of her family history, clinical story, and lack of any medications known to prolong QT intervals, she was suspected to have a congenital adrenergic-dependent form of LQTS. Beta-blocker therapy was initiated while in the hospital. An extensive discussion about the long-term risks associated with LQTS occurred between the patient and the cardiologist during her admission, and she was additionally offered a defibrillator and further outpatient ambulatory telemetry monitoring. She was discharged to home to be followed up by her primary care provider and an outpatient cardiologist in order to assess her response to the initiation of therapy. Other members of her family, in particular her brother, were encouraged to seek consultation for LQTS.