Tuesday, October 29, 2019

Curtailment of EEG monitoring of neonates on therapeutic hypothermia for hypoxic-ischemic encephalopathy

The early background EEG pattern among neonates whose hypoxic-ischemic encephalopathy (HIE) is treated with therapeutic hypothermia (TH) can help guide how long children need to be monitored with continuous EEG, according to findings presented here at the annual meeting of the Child Neurology Society.

Researchers said the findings point to the potential to greatly shorten the period in which children are monitored at some centers and could help save resources.

Many centers—including the University of Michigan, where the study was conducted—provide continuous EEG monitoring throughout the cooling period of 72 hours and through the re-warming period, for a total of about 84 hours. But many children, according to the retrospective cohort study of 114 neonates, had no seizures and, if they did, most had seizure onset within the first 24 hours of monitoring, said Giulia Benedetti, MD, assistant professor of neurology at Seattle Children's Hospital, who worked on the study while at the University of Michigan.

The study included 114 consecutive neonates who were at least 36 weeks of gestational age and were treated with TH for suspected moderate or severe neonatal HIE. Investigators who were blinded to the children's clinical course reviewed archived clips from the first 24 hours of continuous EEG, and this background was classified as normal or mildly abnormal, moderately abnormal, or markedly abnormal based on an assessment of continuity, amplitude, symmetry, synchrony, epileptiform abnormalities, among other measures.

Seizures were more common among those children with markedly abnormal background EEG: 78 percent had seizures compared with 41 percent among those with moderately abnormal backgrounds and 33 percent with normal or mildly abnormal background EEG (p< .001).

Sixty-seven percent of children with normal or mildly abnormal EEG backgrounds did not have seizures at all, and for the 33 percent who did, seizure onset occurred within the first 24 hours of EEG monitoring.

Only 3.5 percent had seizure onset within 24 to 48 hours, and they all had markedly abnormal early continuous EEG backgrounds.

In three cases, seizure onset came after more than 72 hours. Dr. Benedetti noted that two of these cases were not typical HIE: one child had a markedly abnormal background and was ultimately diagnosed with Ohtahara syndrome—early infantile epileptic encephalopathy—and died from uncontrolled seizures; another had a likely genetic metabolic disorder and died from multisystem organ failure, she said. The third was a more typical case, but after re-warming the child had a cluster of seizures, and at six-month follow-up was developing normally.

The message from those cases, Dr. Benedetti said, is that "if the background is moderately or more severely abnormal, then the [children] are still at risk for the late-onset seizures."

Those in whom seizures began after 72 hours gave telltale signs, she noted. "They all had some kind of clinical correlate at some point with their seizures—like an arm jerk that went along with their seizures," she said.

Dr. Benedetti proposed a tailored approach to the duration of EEG monitoring based on the initial EEG background. If an infant has a normal or mildly abnormal early background and no seizures at 24 hours, that baby can be disconnected from monitoring. Alternatively, if a baby has a moderately or markedly abnormal early background, they should be monitored through cooling and re-warming.

"Continuous EEG monitoring through cooling and re-warming takes a lot of time and uses a significant amount of resources," Dr. Benedetti said. "These data suggest that if, at the 24-hour mark, a baby has a mildly abnormal background and no seizures, it is quite safe to disconnect and there is a very low risk of missing late-onset seizures."

Commenting on the study, Patricia K. Crumrine, MD, FAAN, a pediatric neurologist and professor of pediatrics at the Children's Hospital of Pittsburgh, said that the findings make a persuasive case for using continuous EEG monitoring more sparingly, even if a larger sample size would be better for more completely assessing the safety of discontinuing monitoring after 24 hours for some patients.

She said the findings are strong because of the many parameters that were considered.

"They're talking not only of background, but the synchrony between the two hemispheres, the symmetry between the two hemispheres, and the fact that there aren't EEG seizure discharges that you're seeing (during interictal periods)."

She said infants are monitored through re-warming at her center, but that it might be reasonable to re-think that approach in some cases.


The clinical effectiveness of high-priced new therapies for Duchenne muscular dystrophy

Just how clinically effective are three newer therapies for Duchenne muscular dystrophy (DMD) and are they cost-effective? The answers to those questions vary, interviews with neuromuscular experts and patient advocates, and a report from a drug pricing watchdog reveal.

What most will agree on, however, is that advances in DMD therapies have been fast and furious in recent years and that access to these therapies, due to their high cost and other restrictions, will continue to be a challenge.

In the last three years alone, the US Food and Drug Administration (FDA) has approved two of three marketing applications for DMD treatments: Eteplirsen (Exondys 51), the first disease-modifying drug for DMD, was approved in September 2016, for DMD patients who have mutations amenable to exon 51 skipping. Deflazacort (Emflaza), the first corticosteroid option other than prednisone, was approved in February 2017; previously, it was available in the US only by importing it from other countries.

And on August 19, the FDA reviewed but rejected an application for golodirsen (Vyondys 53), developed for patients with a confirmed mutation amenable to exon 53 skipping. The FDA in its response letter cited concerns about the drug's risk of infections related to intravenous infusion ports and renal toxicity,

The decision caught its drug manufacturer Sarepta by surprise. “Renal toxicity with golodirsen was observed in pre-clinical models at doses that were ten-fold higher than the dose used in clinical studies,” Sarepta said in a statement following the FDA decision. Renal toxicity was not observed in the study on which the golodirsen application was based, it said, adding that the drug maker would “address the issues raised in the [FDA] letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen.”

The ICER Report

The setback for the third therapy came days after an August 15 report by the Institute for Clinical and Economic Review (ICER), which concluded that golodirsen and the two other DMD therapies did not live up to their billing.

ICER found deflazacort may be superior to prednisone, but needs a price cut of at least 73 percent to be deemed cost-effective. And it said the exon-skipping therapies—eteplirsen and golodirsen—cannot be assessed for cost-effectiveness because “no persuasive evidence yet exists to demonstrate the clinical effectiveness of either drug.”

ICER did not express concerns about golodirsen's toxicity; the FDA, in its letter rejecting Sarepta's marketing application, did not express concerns about its effectiveness.

ICER had published its views in preliminary form in July. In response, PTC Therapeutics, which makes deflazacort, and Sarepta, the manufacturer of the two exon-skipping therapies, opted not to attend the July 25 meeting at which ICER's New England Comparative Effectiveness Public Advisory Council discussed the assessment.

Instead, Sarepta issued a press release calling ICER's approach to assessing treatments for rare diseases “fatally flawed”: “As a result, we have chosen not to participate in reviews by ICER until it adapts its model to address the inherent limitations and biases that compromise its evaluations of therapies intended to treat patients with serious, rare diseases.”

At its meeting in July, ICER used two empty chairs at the table to make the drug makers' absence clear.

Steven Pearson, MD, ICER's founder and chairman, lamented that, three years after winning controversial approval from the FDA for eteplirsen, Sarepta had not published evidence showing clinical effectiveness, even though its list price for the therapy exceeds $1 million.

“...this is the weakest effort I've ever seen for a company to try to do good research and bring it to the FDA,” he said.

Patient advocate Mindy Leffler disagreed, adding that ICER's assessment, which might spur insurers to deny coverage of FDA-approved DMD treatments, should have been postponed until more evidence is assembled...

The ICER report agreed that published evidence for the three therapies was lacking. In its review, ICER found that deflazacort was no more effective on three attributes—improved muscle strength, improved motor function, and pulmonary function—than prednisone, although deflazacort may be more effective in delaying loss of ambulation. Deflazacort has a different side-effect profile than prednisone, ICER said, including lower rates of undesired weight gain.

Before its FDA approval, deflazacort was available to be imported from other countries for about $1,000 a year. Since its approval in the US, many insurers cover the treatment, but they often either require prior authorization or that patients try less-costly prednisone first.

In ICER's view, its benefits do not justify its US list price—$117,400 per year—or even its net price (what it actually costs, on average, after discounts and rebates) of $81,400 per year. Rather, based on the benefits it offers to patients, ICER said a fair price would be $19,900 to $31,700 annually, according to its cost-effectiveness methodology.

ICER said both eteplirsen and golodirsen have been shown to increase production of dystrophin, which is deficient in DMD, although dystrophin levels remained very low. The best results were for golodirsen, according to the report; at 48 weeks, the mean level of dystrophin had increased to 1.019 percent of normal. There is no validated threshold in dystrophin levels associated with meaningful clinical improvement, ICER said. Further, it found no evidence demonstrating improvements in muscle strength, motor function, ambulation, or pulmonary function.

Advocates Push Against ICER

But some advocates question the outcome measures used in clinical trials, such as time from supine to standing, time to climb four stairs, or the 6-minute walk test. Brian Denger, whose two sons were diagnosed with DMD, said: “A significant proportion of the (DMD) community are off their feet, but are they any less valuable to their family members and the community? I would say no.”

Leffler said patients with DMD want to be able to move their bodies so they can preserve a degree of independence. Outcome measures based on timed performance are off point, she said.

“As my son will say, ‘Nobody cares about speed walking. I never wanted to speed walk and don't have any desire to do so. And it has nothing to do with my quality of life,’” she said...
Leffler showed videos, taken over seven months, that showed her son regain the ability to get into a car independently after receiving eteplirsen. That is not an outcome measure that a clinical trial would use—or that ICER considered in its assessment—but it is an outcome that is meaningful to a patient, she said. 

Robert C. Griggs, MD, FAAN, a University of Rochester neurology professor who has directed a National Institutes of Health-funded training program in the Experimental Therapeutics of Neurological Disease for three decades, is convinced that eteplirsen and golodirsen are clinically effective.

“The evidence was less good for eteplirsen at the time of the (FDA) approval, but there's been subsequent evidence that is more impressive,” he said. “For (golodirsen), the evidence is very impressive.”

Peter Karachunski, MD, clinical director of the Paul and Sheila Wellstone Muscular Dystrophy Center at the University of Minnesota Medical School, said the high cost of eteplirsen has not been a barrier for most of his patients who are eligible because their insurers have approved coverage.

“My problem with the drug is not necessarily its cost; it's that it is really hard to see any perceptible benefit,” he said. “You just have to believe that it's working for any given person. So that's the challenge.”


Monday, October 28, 2019

SETD2 related overgrowth syndrome

Marzin P, Rondeau S, Aldinger KA, Alessandri JL, Isidor B, Heron D, Keren B, Dobyns WB, Cormier-Daire V. SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature. Am J Med Genet C Semin Med Genet. 2019 Oct 23. doi: 10.1002/ajmg.c.31746. [Epub ahead of print]

The common genes responsible for overgrowth syndromes play key roles in regulating transcription through histone modification and chromatin modeling. The SETD2 gene encoding a H3K36 trimethyltransferase is implicated in Sotos-like syndrome. This syndrome is characterized by postnatal overgrowth, macrocephaly, obesity, speech delay, and advanced carpal ossification. We report four new patients with constitutional SETD2 mutations and review nine earlier reported patients. Almost all patients presented with macrocephaly associated with advanced stature and obesity in half of the cases. In addition to these principal manifestations, neurodevelopmental disorders are common such as intellectual disability (83%), autism spectrum disorders (89%), and behavioral difficulties (100%) with aggressive outbursts (83%). A variety of features such as joint hypermobility (29%), hirsutism (33%), and naevi (50%) were also reported. Constitutional SETD2 mutations are intragenic loss-of-function variants with truncating (69%) and missense (31%) mutations. Functional studies are necessary to improve understanding of the pathogenicity of some missense SETD2 mutations.

See: https://childnervoussystem.blogspot.com/2015/12/autism-and-single-nucleotide-variants.html 

Friday, October 25, 2019


Dreissen YEM, Cath DC, Tijssen MAJ. Functional jerks, tics, and paroxysmal movement disorders. Handb Clin Neurol. 2016;139:247-258.

Functional jerks are among the most common functional movement disorders. The diagnosis of functional jerks is mainly based on neurologic examination revealing specific positive clinical signs. Differentiation from other jerky movements, such as tics, organic myoclonus, and primary paroxysmal dyskinesias, can be difficult. In support of a functional jerk are: acute onset in adulthood, precipitation by a physical event, variable, complex, and inconsistent phenomenology, suggestibility, distractibility, entrainment and a Bereitschaftspotential preceding the movement. Although functional jerks and tics share many similarities, characteristics differentiating tics from functional jerks are: urge preceding the tic, childhood onset, rostrocaudal development of the symptoms, a positive family history of tics, attention-deficit hyperactivity disorder or obsessive-compulsive symptoms, and response to dopamine antagonist medication. To differentiate functional jerks from organic myoclonus, localization of the movements can give direction. Further features in support of organic myoclonus include: insidious onset, simple and consistent phenomenology, and response to benzodiazepines or antiepileptic medication. Primary paroxysmal dyskinesias and functional jerks share a paroxysmal nature. Leading in the differentiation between the two are: a positive family history, in combination with video recordings revealing a consistent symptom pattern in primary paroxysmal dyskinesias. In this chapter functional jerks and their differential diagnoses will be discussed in terms of epidemiology, symptom characteristics, disease course, psychopathology, and supportive neurophysiologic tests.

Demartini B, Ricciardi L, Parees I, Ganos C, Bhatia KP, Edwards MJ. A positive diagnosis of functional (psychogenic) tics. Eur J Neurol. 2015 Mar;22(3):527-e36. 

Functional tics, also called psychogenic tics or pseudo-tics, are difficult to diagnose because of the lack of diagnostic criteria and their clinical similarities to organic tics. The aim of the present study was to report a case series of patients with documented functional tics and to describe their clinical characteristics, risk factors and psychiatric comorbidity. Also clinical tips are suggested which might help the differential diagnosis in clinical practice.

Eleven patients (mean age at onset 37.2, SD 13.5; three females) were included with a documented or clinically established diagnosis of functional tics, according to consultant neurologists who have specific expertise in functional movement disorders or in tic disorders. Adult onset, absent family history of tics, inability to suppress the movements, lack of premonitory sensations, absence of pali-, echo- and copro-phenomena, presence of blocking tics, the lack of the typical rostrocaudal tic distribution and the coexistence of other functional movement disorders were common in our patients.

Our data suggest that functional tics can be differentiated from organic tics on clinical grounds, although it is also accepted that this distinction can be difficult in certain cases. Clinical clues from history and examination described here might help to identify patients with functional tics.

Versace V, Campostrini S, Sebastianelli L, Soda M, Saltuari L, Lun S, Nardone R, Kofler M. Adult-Onset Gilles de la Tourette Syndrome: Psychogenic or Organic? The Challenge of Abnormal Neurophysiological Findings. Front Neurol. 2019 May 3;10:461.

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and vocal tics. Adult-onset cases are rare and may be due to "reactivation" of childhood tics, or secondary to psychiatric or genetic diseases, or due to central nervous system lesions of different etiologies. Late-onset psychogenic motor/vocal tics resembling GTS have been described. Neurophysiology may serve to differentiate organic from functional GTS. Altered blink reflex pre-pulse inhibition (BR-PPI), blink reflex excitability recovery (BR-ERC), and short-interval intracortical inhibition (SICI) have been described in GTS. We report a 48-years-old male, who developed numerous motor/vocal tics 2 months after sustaining non-commotional craniofacial trauma in a car accident. Both his father and brother had died earlier in car crashes. He presented with blepharospasm-like forced lid closure, forceful lip pursing, noisy suction movements, and deep moaning sounds, occurring in variable combinations, without warning symptoms or internal "urge." Tics showed low distractibility and these increased with attention. Standard magnetic resonance imaging, electroencephalography, and evoked potentials were unremarkable. Neuropsychology diagnosed moderately impaired intellect, attention, and executive functions. Psychiatric assessment revealed somatization disorder and generalized anxiety. BR-PPI was unremarkable, while BR-ERC was enhanced, even showing facilitation at short intervals. SICI was markedly reduced at 1 and 3 ms and intracortical facilitation (ICF) was enhanced at 10 ms. The patient fulfilled Fahn and Williams' diagnostic criteria for a psychogenic movement disorder. Neurophysiology, however, documented hyperexcitability of motor cortex and brainstem. We suggest that-similar to what has been reported in psychogenic dystonia-a pre-existing predisposition may have led to the functional hyperkinetic disorder in response to severe psychic stress.

Tan EK. Psychogenic tics: diagnostic value of the placebo test. J Child Neurol. 2004 Dec;19(12):976-7.

Motor tics are characterized by abrupt onset of brief, unsustained focal movements that are usually preceded by a premonitory sensation and are suppressible. Psychogenic tics (pseudotics) are rarely described. It may not be easy to distinguish organic from functional tics because they can coexist. Using a case illustration, the value of a "staged" placebo test in aiding the diagnosis of psychogenic tics is described. In addition, a concise summary of the clinical phenomenology of tics and the diagnosis and management of psychogenic movement disorders is provided.

Sunday, October 20, 2019

Prenatal maternal anemia and preeclampsia autism risk

Wiegersma AM, Dalman C, Lee BK, Karlsson H, Gardner RM. Association of Prenatal Maternal Anemia With Neurodevelopmental Disorders. JAMA Psychiatry. 2019 Sep 18:1-12. doi: 10.1001/jamapsychiatry.2019.2309. [Epub ahead of print]


Given the critical role that iron plays in neurodevelopment, an association between prenatal iron deficiency and later risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), is plausible.

To test the a priori hypothesis that anemia diagnosed in mothers during pregnancy is associated with an increased risk of ASD, ADHD, and ID in offspring and that the magnitude of the risk varies with regard to the timing of anemia in pregnancy.

This cohort study used health and population register data from the Stockholm Youth Cohort to evaluate 532 232 nonadoptive children born from January 1, 1987, to December 31, 2010, in Sweden, with follow-up in health registers until December 31, 2016. Data analysis was performed from January 15, 2018, to June 20, 2018.

Registered diagnoses of anemia during pregnancy. Gestational timing of the first recorded anemia diagnosis (≤30 weeks or >30 weeks) was considered to assess potential critical windows of development.

Registered diagnoses of ASD, ADHD, or ID or co-occurring combinations of these disorders.

The cohort included 532 232 individuals (272 884 [51.3%] male) between 6 and 29 years of age at the end of follow-up (mean [SD] age, 17.6 [7.1] years) and their 299 768 mothers. The prevalence of ASD, ADHD, and ID was higher among children born to mothers diagnosed with anemia within the first 30 weeks of pregnancy (4.9% ASD, 9.3% ADHD, and 3.1% ID) compared with mothers with anemia diagnosed later in pregnancy (3.8% ASD, 7.2% ADHD, and 1.1% ID) or mothers not diagnosed with anemia (3.5% ASD, 7.1% ADHD, and 1.3% ID). Anemia diagnosed during the first 30 weeks of pregnancy but not later was associated with increased risk of diagnosis of ASD (odds ratio [OR], 1.44; 95% CI, 1.13-1.84), ADHD (OR, 1.37; 95% CI, 1.14-1.64), and ID (OR, 2.20; 95% CI, 1.61-3.01) in offspring in models that included socioeconomic, maternal, and pregnancy-related factors. Early anemia diagnosis was similarly associated with risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) in a matched sibling comparison. Considering mutually exclusive diagnostic groups, we observed the strongest association between anemia and ID without co-occurring ASD (OR, 2.72; 95% CI, 1.84-4.01). Associations of these disorders with anemia diagnosed later in pregnancy were greatly diminished.

In contrast to maternal anemia diagnosed toward the end of pregnancy, anemia diagnosed earlier in pregnancy was associated with increased risk of the development of ASD, ADHD, and particularly ID in offspring. Given that iron deficiency and anemia are common among women of childbearing age, our findings emphasize the importance of early screening for iron status and nutritional counseling in antenatal care.

Maher GM, O'Keeffe GW, Dalman C, Kearney PM, McCarthy FP, Kenny LC, Khashan AS. Association between preeclampsia and autism spectrum disorder: a population-based study. J Child Psychol Psychiatry. 2019 Sep 17. doi:10.1111/jcpp.13127. [Epub ahead of print]


The environmental contribution of autism spectrum disorder (ASD) is approximately 17%-50%, highlighting the importance of investigating factors potentially contributing to the likelihood of its development, and of gaining a greater understanding of the pathogenesis surrounding ASD. The objective of this study was to examine the association between preeclampsia and ASD using a population-based cohort study.

All singleton live births in Sweden from 1982 to 2010 were included, using data from Swedish National Registers. Exposures of interest included: (a) preeclampsia (classified according to ICD-8, ICD-9 and ICD-10) and (b) preeclampsia and small for gestational age (SGA) combined, used as a proxy for preeclampsia with placental dysfunction. ASD status was based on ICD-9 and ICD-10. The cohort consisted of 2,842,230 children, with 54,071 cases of ASD. Follow-up began from the child's first birthday, and data were censored at first diagnosis of ASD, death, migration or end of study period (31st December 2016). We conducted multivariate Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors, selected a priori. We further controlled for shared genetic and familial confounding using sibling-matched analysis.

In the adjusted Cox proportional hazards regression analysis, preeclampsia was associated with a 25% increase in the likelihood of ASD (Hazard Ratio (HR): 1.25, 95% CI:1.19, 1.30) compared with those unexposed to preeclampsia, while in the sibling-matched analysis the HR was 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling-matched analysis.

Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ASD. The stronger association with preeclampsia/SGA than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD.

Friday, October 18, 2019

Cortical stimulation-induced seizures versus spontaneous seizures for epilepsy surgery planning

Cuello Oderiz C, von Ellenrieder N, Dubeau F, Eisenberg A, Gotman J, Hall J, Hincapié AS, Hoffmann D, Job AS, Khoo HM, Minotti L, Olivier A, Kahane P, Frauscher B. Association of Cortical Stimulation-Induced Seizure With Surgical Outcome in Patients With Focal Drug-Resistant Epilepsy. JAMA Neurol. 2019 Jun 10. doi: 10.1001/jamaneurol.2019.1464. [Epub ahead of print]


Cortical stimulation is used during presurgical epilepsy evaluation for functional mapping and for defining the cortical area responsible for seizure generation. Despite wide use of cortical stimulation, the association between cortical stimulation-induced seizures and surgical outcome remains unknown.

To assess whether removal of the seizure-onset zone resulting from cortical stimulation is associated with a good surgical outcome.

This cohort study used data from 2 tertiary epilepsy centers: Montreal Neurological Institute in Montreal, Quebec, Canada, and Grenoble-Alpes University Hospital in Grenoble, France. Participants included consecutive patients (n = 103) with focal drug-resistant epilepsy who underwent stereoelectroencephalography between January 1, 2007, and January 1, 2017. Participant selection criteria were cortical stimulation during implantation, subsequent open surgical procedure with a follow-up of 1 or more years, and complete neuroimaging data sets for superimposition between intracranial electrodes and the resection.

Cortical stimulation-induced typical electroclinical seizures, the volume of the surgical resection, and the percentage of resected electrode contacts inducing a seizure or encompassing the cortical stimulation-informed and spontaneous seizure-onset zones were identified. These measures were correlated with good (Engel class I) and poor (Engel classes II-IV) surgical outcomes. Electroclinical characteristics associated with cortical stimulation-induced seizures were analyzed.

In total, 103 patients were included, of whom 54 (52.4%) were female, and the mean (SD) age was 31 (11) years. Fifty-nine patients (57.3%) had cortical stimulation-induced seizures. The percentage of patients with cortical stimulation-induced electroclinical seizures was higher in the good outcome group than in the poor outcome group (31 of 44 [70.5%] vs 28 of 59 [47.5%]; P = .02). The percentage of the resected contacts encompassing the cortical stimulation-informed seizure-onset zone correlated with surgical outcome (median [range] percentage in good vs poor outcome: 63.2% [0%-100%] vs 33.3% [0%-84.6%]; Spearman ρ = 0.38; P = .003). A similar result was observed for spontaneous seizures (median [range] percentage in good vs poor outcome: 57.1% [0%-100%] vs 32.7% [0%-100%]; Spearman ρ = 0.32; P = .002). Longer elapsed time since the most recent seizure was associated with a higher likelihood of inducing seizures (>24 hours: 64.7% vs <24 hours: 27.3%; P = .04).

Seizure induction by cortical stimulation appears to identify the epileptic generator as reliably as spontaneous seizures do; this finding might lead to a more time-efficient intracranial presurgical investigation of focal epilepsy as the need to record spontaneous seizures is reduced.

Some epileptologists already use cortical stimulation to help define the focal point for surgery, Dr. Frauscher told Neurology Today, but typically patients are put in an EEG monitoring unit to wait for spontaneous seizures to happen so that doctors can pinpoint the seizure-onset zone. She said it may take days, or even weeks, for patients to have a spontaneous seizure, an approach that may be costlier due to lengthy hospital stays and riskier because the implanted electrodes need to remain in place longer.

“These long stays can be inconvenient for patients and expensive for health care systems,” said Dr. Frauscher. “Using induced seizures in this way could reduce the length of hospital stays to just 48-72 hours, which is a game-changer for patients and health care providers.”

The new study was not a randomized trial involving a head-to-head comparison of the two approaches, but it involved a fairly large cohort and produced encouraging results.

Several independent epilepsy experts interviewed by Neurology Today said the new results could cause a shift in the way candidates for epilepsy surgery are evaluated, though they cautioned that the new study included only patients with focal drug-resistant epilepsy and among that group, only those who met the study's strict inclusion criteria. Whether the findings would apply to a broader patient population remains a question.

“I think it is an intriguing study, and it is an area that is relatively understudied despite the fact that intracranial monitoring has been done for years,” said David C. Spencer, MD, FAAN, professor of neurology at Oregon Health & Science University (OHSU) and director of the OHSU Epilepsy Center. “If it is further validated, I think that localization by cortical stimulation could be a very helpful complement to standard assessments. If we could get the same quality of data in a shorter period, it could be positive for both the patient and for medical costs and medical care in general.”…
Seven patients in the total cohort had cortical stimulation-induced seizures but no spontaneous seizures during their presurgical workup.

“That surgical outcomes in this group did not differ from the outcome of the total group suggested that cortical stimulation might be extremely valuable to obtain induced electroclinical seizures and might be used as a substitute for the recording of spontaneous seizures,” the researchers said…
They said that the failure to stimulate seizures in a sizable portion of the 103 patients may be attributed to the fact that “the electrodes were probably placed in a cortical area of high neuronal threshold incapable of sufficiently activating the epileptic network to induce seizures.”

“The absence of cortical-induced seizure might represent a red flag, suggesting the true epileptic zone was missed or only partially sampled,” the study authors said…

Joon-Yi Kang, MD, assistant professor of neurology in the epilepsy center at Johns Hopkins Hospital, said the new report is “very exciting” because “there has always been this question, ‘Can we incorporate information about stimulation induced seizures into our surgical plan?” She said that epilepsy doctors in European epilepsy centers have traditionally been using the approach longer than doctors in the US, who consider spontaneous seizure monitoring the gold standard.

Dr. Kang said that while cortical stimulation is frequently used for functional mapping in epilepsy pre-surgical evaluations, “it hasn't been clear whether stimulation is as good as monitoring for spontaneous seizures, when it comes to pre-surgically defining the target for resection. This paper shows that, yes, it may be as good as passively monitoring patients for seizures in some cases.”

Chrystal M. Reed, MD, PhD, assistant professor of neurology at Cedars-Sinai Medical Center in Los Angeles, said a downside to spontaneous seizure monitoring in an EEG unit is that it may take considerable time for a seizure to occur and show changes on an EEG, even though the patients has been tapered off their antiseizure medication.

“A prolonged period of waiting in an EEG monitoring unit is both time consuming and costly and may increase the risk of infection from having electrodes implanted in the brain for a long time,” she said.

While most patients tend to have spontaneous seizures rather quickly, “some patients are in the monitoring unit for weeks or months,” until a seizure occurs, Dr. Reed said. She said merely taking a patient out of their normal environment may diminish the likelihood of a seizure because the everyday stress that can make patients vulnerable to seizures is absent.


Mosaic trisomy 9

It's true: Not all heroes wear capes. Some are just 3 months old and are already in the fight of their lifetimes. That's the case for Randy James Ahlers - "RJ" - and his parents, Angel and KC Ahlers of Toledo.

By all accounts, Angel's pregnancy was fairly routine and there were no signs that the Ahlers' baby would be anything but healthy. So, it was a shock when RJ was born and doctors discovered he had not one, but two very rare conditions.

The Ahlers' son has Agenesis of the Corpus Callosum or AgCC, and Mosaic trisomy 9. With AgCC, the center of the brain that facilitates communication of the two hemispheres is underdeveloped. About 1 in 4,000 people are born with this. Mosaic trisomy 9 is a rare chromosomal anomaly syndrome. This happens to 1 in 4 million babies.

"Twenty minutes after he was born, the doctors came in and said they wanted an emergency neurological team to look at our son," KC Ahlers said. "They took him from us, and my wife and I were terrified. About an hour and a half later they brought RJ back to us and said the doctor would be in soon to talk with us.

"We were informed that this could mean RJ could have issues seeing, seizures, and mild to severe mental disabilities, and the potential for intellectual disabilities, facial dysmorphism, congenital heart defects, urogenital defects, skeletal defects, and central nervous system defects," KC Ahlers said.

The Ahlers were faced with some very hard to hear facts. Only 50% of children born with the conditions RJ has reach the age of 2. But, the Ahlerses are undaunted - they are exploring every possible option to help their rare son beat the odds. This comes at a steep cost, however. They already have more than $3,000 in accumulative medical bills for his condition from six different specialists, none of whom has ever worked with a Trisomy 9 Mosaic patient. 

"He has medical tests he needs that we have not done yet because we cannot afford them. A DNA/RNA genetic testing of all major organs could locate the areas he has the mutated Trisomy 9. This will let us know what to expect," KC Ahlers said. "This test alone is $10,000 and insurance claims it's not medically necessary. Plus, we have the cost of any future tests and therapy he will need, which is a lot.

"Every day we wake up terrified that this is the day our child will have a hole present itself in one of his organs and bleed out and die. Every cry he makes, we have to worry, 'Is this that moment?' It's like walking in a minefield."

Angel Ahlers says they are willing to do anything for their son, even as medical bills are bankrupting them. They do have medical insurance, and she is a nursing assistant at St. Anne's, but many of RJ's medical tests are being said to be not medically necessary.  

"Just because he is different does not detract our love for him. He has a condition that is rare, and add the AgCC and now he is the rarest of the rare," she said. "We love him so much as the precious, one-of-a-kind treasure that he is, like a 25-carat diamond. How many of those are out there? Same as our son."

The Ahlers family absolutely loves comic books and Halloween - KC and Angel were married on Halloween - and they are combining the two in an effort to raise money to hopefully afford the tests that could extend RJ's odds.

This Saturday, the family and friends will don superhero costumes in honor of their tiny hero, and are asking the community to help fill the buckets for RJ's tests and treatments. They'll be unmistakable in their Marvel and DC Universe costumes at the intersection of Laskey, Tremainsville and Douglas roads in Toledo from 9 a.m. to 5 p.m. If you would like to help, but won't be out and about Saturday, a Go Fund Me has also been established and can be accessed here. 

"He's our fighter," Angel said. "He's our miracle and our gift from God."


Owen Watson has Mosaic Trisomy 9, a rare chromosomal disorder. As a baby, he was failure to thrive. Now, Owen is walking, using sign language and gracing the world with his unbelievably sweet spirit.

Owen Watson is scooting around in a red and yellow car, his sweet face peeking through the open front window.

He climbs out and walks toward the miniature house. He runs through the front door. 

And then Owen starts signing. It’s a hot day outside in the play area of Riley Hospital for Children at IU Health. He wiggles his fist – the sign for a milkshake, which sounds good to Owen right about now. 

Sierra Watson is sitting on a bench, watching her 3-year-old son. She is in awe of all he’s doing. She’s grateful. She’s blessed.

And, yes, she is sad, too.

As Sierra tells the story of Owen’s journey, it is a tale mixed with smiles and tears.

Owen, who turns 4 this month, has Mosaic Trisomy 9 – an extremely rare chromosomal disorder in which the ninth chromosome appears three times rather than twice in some cells of the body.

The condition is so rare that it’s estimated that just 200 to 1,000 people in the world have the syndrome. Owen is believed to be the first known child diagnosed at Riley. Another patient, Ivy Case, also is treated at Riley.

In many cases, children with Mosaic Trisomy 9 have extreme developmental delays. Some never walk or talk. Many have severe intellectual disabilities. The prognosis for Owen is unknown.

And yet Owen, who was labeled failure to thrive as a baby, is at Riley telling strangers “thank you” by touching his fingers to his chin. He can point out colors.

Sierra often finds it hard to believe that Owen is doing so well. He’s had more than a dozen surgeries, plenty of scares and is still nonverbal. Yet, by all measures, Owen is thriving. 

That can be credited to a solid philosophy in the Watson household. Sierra and Owen’s dad, Daniel, do not let his diagnosis define him or get in the way, Owen still has the same expectations as his 6-year-old brother, Cole. 

“We don’t put limits on anything,” Sierra says. “We really push Owen and I think that is part of why he is doing so well.”

Minutes later, Owen smiles. And then he signs: “I want a cheeseburger.”

Her pregnancy with Owen, Sierra says, was textbook. She had plenty of ultrasounds – Sierra is a labor and delivery nurse – and nothing showed up.

Because she’d had a C-section with Cole, Sierra was scheduled for a C-section with Owen. When Owen was born and taken over to the warmer to be checked out by the medical team?

“I could tell something is wrong,” Sierra says, “but they didn’t say anything.”

Eventually, Sierra was told that Owen would need to go to the neonatal intensive care unit for breathing problems. Being a nurse in the field, Sierra didn’t think that was too unusual. 

But several hours later, she learned something different. Owen had a cleft palate. He had a very small jaw, which made it hard for him to breathe.

The original diagnosis: Pierre Robin syndrome – a condition where babies are born with a smaller than normal lower jaw, a tongue that falls back in the throat and difficulty breathing.

Owen was taken by LifeLine ambulance to Riley. The next few weeks were filled with meetings with specialists. 

 And then, when Owen was one month old, “we get this earth shattering diagnosis,” Sierra says. Mosaic Trisomy 9.

Sierra went to Google. The worst-case scenarios popped up. She was devastated. But soon, she found other families from all over the world who had children with Mosaic Trisomy 9.

And their hope gave her hope for Owen.

“He’s the sweetest kid,” Sierra says. “He’s doing really well.” 

Owen’s biggest issues now are feeding and breathing. He uses a feeding tube, but also eats by mouth.

In addition to those cheeseburgers and milkshakes, Owen loves waffles, peanut butter and jelly, all things carbs.

And he works hard to keep getting stronger – in all areas of his life. Owen does physical therapy, feeding therapy and occupational therapy. He practices sign language at home. And Owen goes to preschool.

As Sierra looks back on Owen’s journey, she says it’s so important to remember: “This is your child. It may seem bad at the time, but it’s going to be OK.”

Just look, she says, Owen is living proof.

Advice for parents of children with special needs: “You have to find time to take care of yourself. Even if that means taking a nap or having coffee with friends or going away for the night, your mental health is important,” Sierra says. “Also, you can’t forget about your marriage. Bringing a healthy child into a marriage brings added stress, but throw in health problems and it can be detrimental. You have to find time to be a couple. And when it comes to your child, don’t be afraid to fight for them and to ask questions about anything being done.”

Ivy Case has Trisomy 9 Mosaic, a rare genetic condition with a devastating prognosis. And, yet, Ivy is beating the odds.

Ivy Case is blowing bubbles. Sometimes, if she’s in the mood, she will curl in her lower lip and crack the tiniest of smiles. She has a sweet babble and will squeal if she recognizes a voice.

She also has a G-tube, oxygen, severe vision impairment and a look that, at times, will cause strangers to stare.

Ivy is 10 months old. She was born with a rare genetic condition called Trisomy 9 Mosaic. Google it and the results are devastating and daunting – an unending list of abnormalities and malformations.

Yet, Renee Case saw sweet Ivy on a special needs adoption posting in the summer of 2017.

“And I could not get her out of my mind,” she says. “I just knew there was something there. Now, we tell her that we found each other.”

Ivy is one of just 200 documented cases of Trisomy 9 Mosaic in the world. She is being treated at Riley Hospital for Children at IU Health.

“She’s literally one in 100 million,” Renee Case says.

Ivy’s condition – sometimes called T9M -- is a chromosomal disorder in which the entire ninth chromosome appears three times, rather than twice, in some cells of the body. Mosaic indicates that some cells contain the extra chromosome 9, while others have the typical two chromosomes.

To Renee Case and husband, Joshua, Ivy is perfect. The couple, who live north of Warsaw, Ind., brought her into their home in August.

They had already fallen in love with another child with special needs – their adopted son Jacoby.  And that love prompted them to seek out Ivy.

“It just felt right,” says Joshua Case. It felt right to choose the path of caring for children with special needs. “There is a reason we were supposed to be both of their parents.”

The reason? Well, it’s wonderful and beautiful. Both Jacoby and Ivy are thriving, beating the odds of their prognoses.

“When your kid is blowing bubbles like this, that’s huge for her,” says Renee Case. “It’s about finding the

Take sippy cups. Joshua and Renee went through more sippy cups than they can count to find one that Jacoby, now three years old, would use. His genetic condition causes sensory issues.

They didn’t know they were adopting a child with special needs, not until after Jacoby was born. They met Jacoby when he was two days old in the hospital. He spent 21 days in the neonatal intensive care unit before going home with them.

When he was 9 months old, the Cases decided to do some testing. They knew Jacoby had been born with microcephaly, a condition in which the brain does not develop properly, resulting in a smaller than typical head.

He also had a two-vessel umbilical cord, rather than three vessels, among other issues.

Jacoby’s genetic disorder is called Chromosome 16 p13.11 microdeletion syndrome. It is characterized by developmental delay, microcephaly, epilepsy, short stature, facial dysmorphism and behavioral problems.

And yet, all those things that were supposed to happen with Jacoby either didn’t or are mild, Renee Case says.

He wears braces on his ankles. Jacoby got his first set right before his first birthday and started walking weeks later. He has had some speech issues and, emotionally, he is also delayed.

Yet, Jacoby is doing so many great things. On this day, he is preparing to be line leader at his preschool the next day.

He knows – and talks about – every kind of dinosaur and whale there is.

“He is so incredibly smart,” Renee Case says. “He knows so much for his age.”

It’s evident Joshua and Renee Case are so very proud of their children. They are masters at putting life in perspective.

Besides all those bubbles and smiles, Ivy is starting to roll over a bit from back to side. At 10 months old, she is developmentally at about four months old.

“Which is really good for her diagnosis,” Renee Case says. “She’s just doing so good.”

The Cases didn’t know how Ivy would do when they took her into their home last summer, adopting her from a family in Texas. But they fought to find out.

For the first two months, Ivy had anywhere from two to five appointments every week – doctors, specialists, therapists and evaluations.

What they ultimately discovered was better than expected. Many of the issues, including heart problems, common to Trisomy 9 Mosaic aren’t present with Ivy.

And yet, no matter what might come along for Ivy – or Jacoby --  in the future, Renee and Joshua Case will be there supporting them all the way.

“We were meant to be their parents,” Renee Case says. “We were put into each others’ lives for a reason.”

Tuesday, October 15, 2019

The first drug developed for just one person

Eight-year-old Mila Makovec was diagnosed with a rare, usually fatal neurological disorder in 2016, but now—thanks to a "custom" drug that researchers developed specifically for her—many of Mila's symptoms have been halted or reversed, according to a report published Wednesday in the New England Journal of Medicine.

Mila's condition

Mila's symptoms began when she was three years old. Previously a healthy young girl, she began to suffer from frequent seizures—as many as 30 per day, lasting up to a few minutes each. As the disease progressed, she lost her eyesight, became unable to stand on her own, and ultimately needed a feeding tube.

In December 2016, Mila was diagnosed with Batten's disease, a rapidly progressing neurological disorder. However, Mila's case was unusual, according to doctors. Batten's disease is recessive, which means it occurs when a patient inherits two mutated versions of the MFSD8 gene—but Mila has only one mutated gene. The other was apparently normal, which should have left her unaffected.

Timothy Yu and colleagues at Boston Children's Hospital examined Mila's intact MFSD8 gene, and in March 2017, they found it contained a DNA error that interfered with the production of a key protein.

The good news was that Yu thought he could make a custom piece of RNA to fix the problem. But such a step would be extraordinarily expensive. To support the necessary research, Mila's mother established Mila's Miracle Foundation, and she managed to raise $3 million.

Yu's team was able to develop a new drug, which they called "milasen," after Mila. They tested it in rodents and consulted FDA, which in January 2018 permitted doctors to give the drug to Mila.

Doctors administered the drug via spinal tap so it could go directly into Mila's brain. Within a month, Mila started improving, according to her mother, Julia Vitarello. Mila started having fewer and shorter seizures and now rarely needs her feeding tube. Instead, she's able to eat pureed foods. Mila still can't stand by herself, but when she's held, her neck and back stay straight.

According to the New York Times, Mila remains very disabled, and she has lost the last few words of her vocabulary. Vitarello acknowledged that milasen won't cure Mila, but added that Mila was seven when she received her fist dose. "What if the next Mila is treated when she is four or five?" Vitarello asked, adding that milasen's development "is opening up an entirely new treatment path."

Experts express concern over personalized medicine

Milasen is believed to be the first drug developed for just one person, but Yu and colleagues acknowledged that they're unsure what may come next.

According to Rachel Sher, VP of regulatory and government affairs at the National Organization for Rare Disorders, there are more than 7,000 rare diseases, more than 90% of which have no treatment approved by FDA. That means there may be thousands of patients in a similar situation as Mila, and there aren't enough researchers to design customize drugs for all of them, the Times reports.

And even if there were enough researchers, cost would be a concern, Steven Joffe, professor of medical ethics and health policy at the University of Pennsylvania, said. The government wouldn't pay for the drugs, nor would drug companies or insurers, Joffe said. "Unfortunately, that leaves it to families. It feels awfully uncomfortable, but that is the reality."

Janet Woodcock, director of FDA's Center for Drug Evaluation and Research, expressed concern about how a custom drug's efficacy might be evaluated. As for cost, Woodcock said, "We have to figure it out, collectively, because these people are suffering—many of them children. If we have the scientific ability to develop treatments for these rare diseases, we should find a way to make the financial side of this work" .

Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. Patient-Customized
Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019 Oct 9.
doi: 10.1056/NEJMoa1813279. [Epub ahead of print]

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

Courtesy of a colleague

A 10-year-old boy with fainting spells and seizure activity

Shatha M. Khatib. A 10-Year-Old Boy With Fainting Spells and Seizure Activity - Medscape - Sep 25, 2019. https://reference.medscape.com/viewarticle/884107_1

A 10-year-old boy with a history of multiple fainting spells is brought to an outpatient pediatric clinic by his parents. These spells are sometimes complicated by generalized tonic-clonic "seizurelike" activity.

The patient first started experiencing these attacks 8 months ago. His mother has noticed that the fainting most often occurs either in the early morning, after the sounding of an alarm clock, or during some type of sports activity. The child states that the seizures occur without warning, and they are sometimes associated with urinary incontinence or vomiting. According to the patient's family, the child remains unconscious for about 1 minute, after which he awakens abruptly, with no evidence of confusion and full recall of all of the events preceding the attack. 

The patient was born full-term, without any complications. He has no chronic medical conditions and is not on any medications. As a result of experiencing similar symptoms, his father was diagnosed with epilepsy and started on treatment at age 8 years; however, the father has been without treatment and has not had any attacks since age 14 years. The patient's paternal uncle was also diagnosed with epilepsy at age 10 years; he died during a seizure at age 19 years. The patient has an 8-year-old brother who is well, with no history of seizures or fainting spells.

Physical Examination and Workup

Upon physical examination, the patient is a well-appearing and well-developed boy whose weight and height are in the 50th and 60th percentiles, respectively. His oral temperature is 98.6°F (37°C). His pulse is strong at 66 beats/min, with a regular rhythm. His blood pressure is 105/65 mm Hg, and his respiratory rate is 15 breaths/min.

Head and neck examination findings are normal. The lungs are clear to auscultation, and normal respiratory effort is noted. Cardiac auscultation reveals normal S1 and S2 heart sounds, and no audible murmurs, rubs, or gallops are heard. His abdomen is soft, with no tenderness. No organomegaly is detected. The neurologic examination reveals intact cranial nerves and intact speech. Sensory and motor functions are normal in all extremities, without any pronator drift. The deep tendon reflexes are brisk and symmetric throughout. The patient's Romberg sign is negative, and his gait is stable.

The laboratory analysis, including a complete blood cell count and a basic metabolic panel with serum electrolytes (including calcium and magnesium), is normal. Chest radiography and brain CT findings are also normal. An ECG is obtained (Figure).

The patient's ECG showed a prolonged QT interval (Figure) The corrected QT (QTc) was 0.56 second. In addition, a biphasic T wave was seen in the precordial leads. His father's ECG  also showed a prolonged QT interval (QTc, 0.55 second) and a high-amplitude, rounded T wave in leads V2 and V3. On the ECG of the patient's 8-year-old brother, the QTc was 0.52 second, and T/U wave abnormalities in leads V2 and V3 were also detected.

In the context of the patient's history of recurrent fainting and the family history of "seizures" and sudden death, the prolonged QT intervals noted were very suggestive of intermittent ventricular arrhythmias caused by congenital long QT syndrome (LQTS).

LQTS is an electrical disease of the ventricular myocardium that is characterized by prolonged ventricular repolarization, which results in prolongation of the QT interval on the surface ECG and an increased risk for sudden death. It is characteristically associated with the potentially life-threatening cardiac arrhythmia known as torsade de pointes, which is a form of polymorphic ventricular tachycardia.

A prolonged QT interval may be acquired (usually resulting from drugs or electrolyte disturbances) or congenital. The congenital form is caused by mutations in the gene coding for the cardiac potassium, sodium, or calcium ion channels; about 400 mutations in 10 gene loci have been identified.  The distinct genetic types are designated LQT1-LQT10. LQT1, LQT2, and LQT3 account for over 90% of cases of LQTS, with some estimated prevalences of 45%, 45%, and 7%, respectively.  The specific genotype influences the clinical course, the kinds of triggering events that may initiate arrhythmias, the prognosis, and the recommended form of treatment. An underlying genetic predisposition has been identified in some patients with the acquired form of LQTS.

Traditionally, congenital LQTS has been characterized as two clinical entities:

Romano-Ward syndrome, which is inherited in an autosomal dominant fashion and only has cardiac manifestations.

Jervell and Lange-Nielsen syndrome, which is inherited in an autosomal recessive fashion and is associated with sensorineural deafness.

Most of the epidemiologic and clinical data on congenital LQTS come from reports from the International LQTS Registry. The registry, which began in 1979 and is still ongoing, is a major source of data on the incidence, natural history, and prognosis of patients with congenital LQTS.
The incidence of congenital LQTS is difficult to determine, but it is estimated to be 1 case per 2500-10,000 population, with most estimates around 1 case per 5000 population.[5] The range is broad because a large number of cases go undiagnosed; about 20%-50% of affected patients may not demonstrate QT prolongation on resting ECG. Technical difficulties and methodological controversies in accurately measuring the QT interval are in part to blame. It is nonetheless one of the most common causes of autopsy-negative, unexplained sudden death.

Women are more commonly affected than men. Patients with congenital LQTS usually present in childhood, adolescence, or early adulthood, and they usually present with palpitations, syncope or near syncope, seizures, or cardiac arrest. Syncopal episodes associated with secondary seizures may be misdiagnosed as primary seizure disorders. The seizures are probably secondary to hypoperfusion of the brain during arrhythmic events.

Cardiac dysrhythmias can be initiated by an external trigger, such as emotional stress, exercise, or sudden loud noises (ie, an alarm clock or telephone); however, this is not always the case. Ventricular arrhythmias may also occur during sleep, which is commonly seen in patients with the LQT3 genotype. In fact, the kind of triggering event is often linked to the underlying mutation, with certain triggers more commonly associated with certain genotypes.

As many as 10% of patients are only diagnosed with LQTS at the time of sudden death.[6] Mortality can be as high as 70% in patients who remain untreated over a 10-year period.[3] This emphasizes the importance of presymptomatic diagnosis and treatment. Important clues indicating that a patient may have LQTS include abnormal ECG findings, a family history of unexplained death, or hearing loss (which is present in around 4% of patients with LQTS).

In patients with suspected congenital LQTS, the initial evaluation should be directed at calculating the QTc interval on a resting ECG. The QTc interval is the QT interval corrected for heart rate because, under normal physiologic circumstances, the actual measured QT interval adjusts with the heart rate; in other words, it is longer at slower rates and shorter at faster rates. QTc is calculated by dividing the measured QT by the square root of the R-R interval (the Bazett formula), both of which are measured in seconds…

A scoring system for the diagnosis of congenital LQTS was established in 1985 by Schwartz and colleagues  and revised in 1993 but still serves as the best guide for clinicians today. It incorporates the ECG criteria (the measured resting QTc interval, history of torsade de pointes, presence of T-wave alternans or notched T wave on ECG, and low heart rate for age), the clinical criteria (syncope or congenital deafness), and family history (family members with definite LQTS or unexplained sudden death at < 30 years of age). Points ranging from 0.5 to 3 are assigned to each of the above criteria, and the points are added to calculate the LQTS score. Depending on the patient's score, the probability of having LQTS is rated as low (< 1 point), intermediate (2-3 points), or high (≥ 4 points). Additional testing, such as cold-water facial immersion or exercise testing, may be applied in patients in whom the diagnosis is still unclear.

Genetic testing for congenital LQTS is now available in specialized centers; however, the practical application of genetic testing is limited because of the complexity and heterogeneity of congenital LQTS. In addition, as many as 25% of patients have unknown mutations; therefore, a negative test does not exclude the disease. Once an index case with congenital LQTS is identified, evaluation needs to extend to all first-degree relatives, and treatment must be established where indicated.
The guidelines published by the American College of Cardiology, the American Heart Association, and the European Society of Cardiology consider "lifestyle modifications," defined as the contraindication of competitive sports and of all drugs known to prolong the QT interval, as a class I recommendation and an important strategy for the prevention of fatal arrhythmia in patients with congenital LQTS. The mainstay of medical treatment for LQTS is the use of beta-blockers.  Beta-blockers shorten the QT interval, which decreases the risk for torsade de pointes arrhythmia and reduces the incidence of syncope and sudden cardiac death. They are effective in approximately 70% of patients…

Because of the appreciable risk for torsades de pointes arrhythmia and sudden cardiac death without treatment, all symptomatic patients with congenital LQTS should be treated. Treating asymptomatic patients is more controversial; however, because sudden cardiac death can be the first manifestation of LQTS, a safe approach would be to treat even asymptomatic patients with at least medical therapy.

Thursday, October 10, 2019

Subcortical heterotopic gray matter brain malformations

Oegema R, Barkovich AJ, Mancini GMS, Guerrini R, Dobyns WB. Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals. Neurology. 2019 Oct 1;93(14):e1360-e1373.


To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.

SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.

Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).

This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Lacosamide in pediatric patients with focal seizures

Farkas V, Steinborn B, Flamini JR, Zhang Y, Yuen N, Borghs S, Bozorg A, Daniels T, Martin P, Carney HC, Dimova S, Scheffer IE; SP0969 Study Group. Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures. Neurology. 2019 Sep 17;93(12):e1212-e1226.


To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures.

In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance.

Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%).

Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures.


This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

Monday, October 7, 2019

Posterior reversible encephalopathy syndrome in children

Darwish AH. Posterior Reversible Encephalopathy Syndrome in Children: A Prospective Follow-up Study. J Child Neurol. 2019 Sep 30:883073819876470. doi:10.1177/0883073819876470. [Epub ahead of print]


To evaluate clinical and radiologic presentation, and neurologic outcome of pediatric posterior reversible encephalopathy syndrome (PRES).

The study included 24 children (14 males and 10 females) diagnosed with PRES who were prospectively followed for 2 years. They were evaluated using Wechsler Intelligence Scale, electroencephalograph (EEG), and brain magnetic resonance imaging (MRI).

The mean age of the studied patients at the time of diagnosis of PRES was 6 years (±2.2). Chemotherapy for cancer represented 66.7% of the causes of PRES in the studied children, followed by renal disorders and immunosuppressive agents for hematopoietic stem cell transplantation. Twenty-seven attacks of PRES were reported as 3 children developed a second attack of PRES. Normal intelligence quotient was found in 95.8% of studied children after PRES. Residual abnormalities in follow-up MRI were demonstrated in 3 children. Epilepsy and residual MRI lesions were reported in 2 of the 3 children with recurrent PRES. Residual lesions in follow-up MRI and epilepsy were more significantly reported after recurrent PRES (P < .05).

Neoplastic, renal disorders and hematopoietic stem cell transplantation represent the main disorders associated with PRES in children. Chemotherapeutic drugs, immunosuppressants, and hypertension are the main risk factors for pediatric PRES. The outcome of pediatric PRES is good, but long-term neurologic sequelae can occur, mainly epilepsy and residual MRI abnormalities. Recurrence of PRES is infrequently reported in children receiving chemotherapeutic or immunosuppressive drugs. Recurrent PRES is a risk factor for long-term neurologic sequelae.

Courtesy of:  https://www.mdlinx.com/journal-summaries/pres-chemotherapy-neurologic-sequelae-outcome/2019/10/03/7581028?spec=neurology

Risk factors for perinatal arterial ischaemic stroke

Sorg AL, von Kries R, Klemme M, Gerstl L, Weinberger R, Beyerlein A, Lack N, Felderhoff-Müser U, Dzietko M. Risk factors for perinatal arterial ischaemic stroke: a large case-control study. Dev Med Child Neurol. 2019 Sep 5. doi:10.1111/dmcn.14347. [Epub ahead of print]


To identify maternal, obstetric, and neonatal risk factors related to perinatal arterial ischaemic stroke (PAIS) diagnosed within 28 days after birth and to understand the underlying pathophysiology.

For case and control ascertainment, we used active surveillance in 345 paediatric hospitals and a population-based perinatal database for quality assurance of hospital care. We analysed complete cases of PAIS using logistic regression. Multivariate analysis was guided by a directed acyclic graph.

After exclusion of records with missing data, we analysed 134 individuals with PAIS and 576 comparison individuals. In univariate analysis, male sex, preterm birth (<37wk gestational age), small for gestational age (SGA), low umbilical artery pH (<7.1), low 5-minute-Apgar score (<7), multiple pregnancies, hypoxia, intubation/mask ventilation, nulliparity, Caesarean section, vaginal-operative delivery, chorioamnionitis, and oligohydramnios were associated with an increased risk. Mutual adjustment yielded male sex (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.20-2.73), multiple birth (OR 3.22; 95% CI 1.21-8.58), chorioamnionitis (OR 9.89; 95% CI 2.88-33.94), preterm birth (OR 1.86; 95% CI 1.01-3.43), and SGA (OR 3.05; 95% CI 1.76-5.28) as independent risk factors.

We confirmed the increased risk in males and the role of chorioamnionitis and SGA for PAIS, pointing to the importance of inflammatory processes and fetal-placental insufficiency. Multiple birth and preterm birth were additional risk factors.

Chorioamnionitis and small for gestational age (SGA) precede perinatal arterial ischaemic stroke (PAIS). Chorioamnionitis and SGA are independent risk factors for PAIS. Inflammatory processes and fetal-placental insufficiency are the likely underlying mechanisms. Multiple birth and preterm birth are additional risk factors.

Courtesy of:  https://www.mdlinx.com/journal-summaries/perinatal-arterial-ischaemic-stroke-pathophysiology-hypoxia/2019/09/12/7578095?spec=neurology

Brain tumor presenting as focal epilepsy


Sunday, October 6, 2019

Childhood stroke

When single mom Hayley Clark found her 10-year-old daughter collapsed on the bathroom floor, she never suspected that a stroke was the cause of her “healthy” daughter’s medical scare.

Gracie Whittick, 10, suffered a stroke on Sept. 26 as she was getting ready for school, her mom told South West News Service (SWNS), a British news agency.

"It was all completely out of the blue. There were no warning signs at all, she was fine before. She was getting ready for school and the next second she was on the floor,” she recalled.

"It happened in seconds. I thought she had fainted on the floor and I had to get her to come around. The right side of her face was drooping. She couldn’t lift her arms, move her arms or legs,” she continued, noting she immediately called an ambulance.

Doctors at Queen Elizabeth Hospital King’s Lynn in Norfolk, England, later told confirmed a blood clot on the left side of Gracie’s brain had caused the stroke. The young girl underwent a three-hour surgery to remove 96 percent of the clot. It’s unclear at this time what caused the clot.

"The whole thing is really surreal. Doctors still don't know why it happened; she had a heart scan and that has come back as normal,” she said.

The stroke impacted the right side of her body. The 10-year-old, who is right-handed, now has trouble using her right arm. She’s also struggling with memory issues. She began walking again recently, but tires quickly and will sometimes resort to a wheelchair, her mother said.

"She keeps getting really confused and she is getting frustrated with it all,” she said.

“The whole thing is really surreal. To me, a stroke is an old people thing. It isn’t something that happens to a healthy 10-year-old girl,” Clark added, noting Gracie enjoys dancing and gymnastics.

Though relatively uncommon, pediatric strokes can and do occur. According to the Children’s Hospital of Philadelphia, pediatric stroke affects an estimated 12 in 100,000 children under the age of 18.  However, there may be more cases of pediatric stroke as it is “thought to be frequently undiagnosed or misdiagnosed,” says a 2011 medical review on pediatric stroke.

Children most at risk are those with sickle cell anemia or congenital heart defects and other conditions.

“Previously healthy children who are found to have hidden disorders such as narrow blood vessels or a tendency to form blood clots easily,” are also at risk, according to the hospital.

Gracie is expected to recover but will likely remain in the hospital for another six weeks, SWNS reported.

“She doesn't remember anything, I don't think she understands what happened. She is only 10,” Clark said. "It has been a shock to all of us. It has just been a hideous time. But she has been so lucky with this, it all could've been a lot worse."