Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

OBJECTIVE: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age. METHODS: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin. RESULTS: Of 84 infants enrolled, 12 were screen failures, 4 went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). Fifty-six were randomized to early vigabatrin (n = 29) or placebo (n = 27). Nineteen of 27 in the placebo arm transitioned to open label vigabatrin, with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug-resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups. INTERPRETATION: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children, nor does it delay onset or lower the incidence of focal seizures and drug-resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. ANN NEUROL 2023.

X-ray detection of a nova in the fireball phase.

Novae are caused by runaway thermonuclear burning in the hydrogen-rich envelopes of accreting white dwarfs, which leads to a rapid expansion of the envelope and the ejection of most of its mass1,2. Theory has predicted the existence of a 'fireball' phase following directly on from the runaway fusion, which should be observable as a short, bright and soft X-ray flash before the nova becomes visible in the optical3-5. Here we report observations of a bright and soft X-ray flash associated with the classical Galactic nova YZ Reticuli 11 h before its 9 mag optical brightening. No X-ray source was detected 4 h before and after the event, constraining the duration of the flash to shorter than 8 h. In agreement with theoretical predictions4,6-8, the source's spectral shape is consistent with a black-body of 3.27+0.11-0.33 × 105 K (28.2+0.9-2.8 eV), or a white dwarf atmosphere, radiating at the Eddington luminosity, with a photosphere that is only slightly larger than a typical white dwarf.

Painful, reappearing eruption in a medically complex 4-year-old.

A 4-year-old boy with atypical, complete DiGeorge and CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities and ear abnormalities) syndromes presented with frequent episodes of a painful, markedly erythematous eruption associated with swelling. Evaluation revealed non-specific findings on skin biopsy at the time of eruption and no pathogenic mutation in the SCN9A gene. The patient was diagnosed with secondary erythromelalgia based on clinical presentation. Erythromelalgia is a rare disorder characterised by recurrent episodes of pain and erythema typically affecting the distal extremities. This case represents the first case of erythromelalgia in the setting of DiGeorge and CHARGE syndromes.

Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies.

Leukodystrophies are a group of neurodegenerative genetic disorders that affect approximately 1 in 7500 individuals. Despite therapeutic progress in individual leukodystrophies, guidelines in neurologic care are sparse and consensus among physicians and caregivers remains a challenge. At patient advocacy meetings hosted by Hunter's Hope from 2016-2018, multidisciplinary experts and caregivers met to conduct a literature review, identify knowledge gaps and summarize best practices regarding neurologic care. Stages of severity in leukodystrophies guided recommendations to address different levels of need based on a newly defined system of disease severity. Four core neurologic domains prioritized by families were identified and became the focus of this guideline: sleep, pain, seizures/epilepsy, and language/cognition. Based on clinical severity, the following categories were used: presymptomatic, early symptomatic, intermediate symptomatic, and advanced symptomatic. Across the leukodystrophies, neurologic care should be tailored to stages of severity while accounting for unique aspects of every disease and multiple knowledge gaps present. Standardized tools and surveys can help guide treatment but should not overburden families.

Correction to: Intravenous Migraine Treatment in Children and Adolescents.

The original publication of this article unfortunately contained the incorrect version of the manuscript. The original article has been corrected.

Intravenous Migraine Treatment in Children and Adolescents.

PURPOSE OF REVIEW: Pediatric migraine is a common, chronic, and disabling neurological disorder in children and adolescents. Outpatient management is not always effective, and intravenous migraine management may be necessary for headache treatment in the pediatric emergency department. Most current treatment is based on retrospective evidence and there is a lack of well-designed randomized double-blinded controlled pediatric studies. Intravenous drug treatment agents including intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine are reviewed in this paper. RECENT FINDINGS: Nineteen studies were reviewed including one prospective randomized double-blind; one single-blinded randomized; one prospective; and one open-label, randomized clinical trial. Most studies were retrospective and the quality of the studies was limited. No definite conclusions can be drawn from the studies, but appropriate prospective trials between major pediatric headache institutions will move pediatric intravenous migraine management forward.

Further Evidence that Onabotulinum Toxin is a Viable Treatment Option for Pediatric Chronic Migraine Patients.

Introduction Chronic migraine is particularly devastating. It affects school work, extracurricular activities, and quality of life, including relationships with other family members, and can also influence the mental health of both the migraineurs and family members. According to the International Classification of Headache Disorders, 3rd edition (ICHD-3), chronic migraine is defined as 15 or more headache days per month for greater than three months, where at least on eight days per month, there are features of migraine headache. Although botulinum toxin type A (BoNTA) has been proven effective for treating chronic migraine in adults, little literature exists about its use in children. Here, we present the treatment response in children with chronic migraines treated with BoNTA at our institutions Duke and State University of New York (SUNY) Upstate. Method A retrospective analysis of 30 adolescent migraineurs who met ICHD-3 criteria for chronic migraine were treated with BoNTA injection according to the standardized adult protocol. Descriptive statistics and paired t-tests were performed. A total of 185 units of botulinum toxin were injected intramuscularly per patient, as in addition to the standard 31 sites for a total of 155 units, an additional 30 units were given in areas that were felt to provide further benefit. Results Participants (n=30) were 16.5 ± 1.83 years old. The headaches were precipitated by trauma in seven cases. All had failed standard pharmacotherapy, including amitriptyline and topiramate. An average of 2.47 ± 1.6 BoNTA injection cycles was performed. Migraine severity decreased significantly from 7.47 ± 1.89 on a 10-point scale to 4.34 ± 3.02 (p<.001). Additionally, headache frequency improved from 24.4 ± 7.49 painful days per month to 14.8 ± 12.52 painful days per month (p<.001). One patient developed nausea related to injections; all others tolerated it well, with no side effects. Discussion BoNTA injection was a safe and effective therapy for chronic migraine in our cohort of children recalcitrant to medical therapy. Further research with multi-centered, double-blinded, randomized, placebo-controlled trials is warranted to evaluate the long-term safety and efficacy in this population.

MRI-guided laser interstitial thermal therapy in an infant with tuberous sclerosis: technical case report.

Cortical tubers associated with tuberous sclerosis complex (TSC) are potential epileptic foci that are often amenable to resective or ablative surgeries, and controlling seizures at a younger age may lead to improved functional outcomes. MRI-guided laser interstitial thermal therapy (MRgLITT) has become a popular minimally invasive alternative to traditional craniotomy. Benefits of MRgLITT include the ability to monitor the ablation in real time, a smaller incision, shorter hospital stay, reduced blood loss, and reduced postoperative pain. To place the laser probe for LITT, however, stereotaxy is required-which classically involves head fixation with cranial pins. This creates a relative minimum age limit of 2 years old because it demands a mature skull and fused cranial sutures. A novel technique is presented for the application of MRgLITT in a 6-month-old infant for the treatment of epilepsy associated with TSC. To the authors' knowledge this is the youngest patient treated with laser ablation. The authors used a frameless navigation technique with a miniframe tripod system and intraoperative reference points. This technique expands the application of MRgLITT to younger patients, which may lead to safer surgical interventions and improved outcomes for these children.

Child Neurology: An infant with episodic facial flushing: A rare case and review of congenital harlequin syndrome.

Congenital harlequin syndrome is rare dysautonomia of the face most often reported in adults and rarely in infants and children. It is a diagnosis of exclusion and a seemingly benign condition. We report a case of a 6-month-old girl with episodic unilateral and bilateral facial flushing provoked upon awakening and resolved with sleeping with associated autonomic features consistent with harlequin syndrome. This is followed by a review of cases identified regarding this condition in infants and children.

Recruitment & retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA!

BACKGROUND/AIMS: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. METHODS: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. RESULTS: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. CONCLUSIONS: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

Natural history of infantile-onset spinal muscular atrophy.

OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.

Auditory processing following infantile spasms: An event-related potential study.

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study.

OBJECTIVE: This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA). METHODS: This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. RESULTS: Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high-frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. INTERPRETATION: By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

Discordant cardiac biomarker levels independently predict outcome in ST-segment elevation myocardial infarction.

AIMS: To investigate the prognostic relevance of elevated Troponin T (cTnT) levels in patients with ST-segment elevation myocardial infarction (STEMI) without significant creatine kinase (CK) elevation on admission. METHODS AND RESULTS: From January 1, 2002 to December 31, 2006 patients with STEMI without significant CK elevation (<2-fold) on admission treated with percutaneous coronary intervention (PCI) were included and stratified according to cTnT plasma levels. Univariate and multivariate regression analyses were used to find independent predictors for mortality. During the 5-year period 514 patients with STEMI and normal CK plasma levels were included. 308 (59.9 %) patients had cTnT levels <0.1 µg/l and 206 (40.1 %) patients had cTnT levels ≥0.1 µg/l. Multivariate logistic regression analysis identified cTnT levels ≥0.1 µg/l and 3-vessel disease as positive, and hemoglobin levels as negative independent predictors for long-term mortality. Discordantly elevated cTnT plasma levels independently predicted higher mortality rates in the first year (HR 3.9, 95 % CI 1.7-9.1, p = 0.002) and during 5 years (HR 2.3, 95 % CI 1.4-3.9, p = 0.002) after PCI for STEMI. CONCLUSIONS: Discordant elevation of cTnT in the presence of normal CK plasma levels on admission is associated with increased mortality in STEMI patients undergoing primary PCI. This may be due to preceding microembolization.

Temporal lobe impairment in West syndrome: event-related potential evidence.

OBJECTIVE: This study investigates auditory processing in infants with West syndrome (WS) using event-related potentials (ERPs). METHODS: ERPs were measured in 25 infants with mainly symptomatic WS (age range = 3-10 months) and 26 healthy term infants (age range = 3-9 months) using an auditory novelty oddball paradigm. The ERP recordings were made during wakefulness and repeated in stage II sleep. RESULTS: The obligatory components (P150, N250, P350) and novelty response components (P300, Nc) were recordable during both sleep and wakefulness in patients and controls. All ERP latencies decreased with age in controls but not in the WS group (age × group interaction, F = 22.3, p < 0.0001). These ERP latency alterations were not affected by pharmacological treatment for WS. INTERPRETATION: This study demonstrated a persistently altered ERP signature in patients with a recent history of infantile spasms. The prolongation of auditory obligatory and novelty ERPs in WS patients indicates a severe failure of temporal lobe maturation during infancy. It remains to be investigated whether this predicts long-term cognitive impairments characteristic for this epileptic encephalopathy.

Heavy quark energy loss in high multiplicity proton-proton collisions at the LHC.

One of the most promising probes to study deconfined matter created in high energy nuclear collisions is the energy loss of (heavy) quarks. It has been shown in experiments at the Relativistic Heavy Ion Collider that even charm and bottom quarks, despite their high mass, experience a remarkable medium suppression in the quark gluon plasma. In this exploratory investigation we study the energy loss of heavy quarks in high multiplicity proton-proton collisions at LHC energies. Although the colliding systems are smaller than compared to those at the Relativistic Heavy Ion Collider (p+p vs Au+Au), the higher energy might lead to multiplicities comparable to Cu+Cu collisions at the Relativistic Heavy Ion Collider. The interaction of charm quarks with this environment gives rise to a non-negligible suppression of high momentum heavy quarks in elementary collisions.

Direct photons at low transverse momentum: a signal for quark-gluon plasma in pp collisions at LHC.

We investigate photon production in a scenario of quark-gluon plasma formation in proton-proton scattering at 7 TeV. It is shown that thermal photon yields increase quadratically with the charged particle multiplicity. This gives an enhanced weight to high multiplicity events, and leads to an important photon production even in minimum-bias events, where the thermal photons largely dominate over the prompt ones at transverse momentum values smaller than 10 GeV/c.

Retrieval of lost coronary guidewires during challenging percutaneous coronary interventions.

INTRODUCTION: The presence of symptomatic or asymptomatic intravascular/intracardiac foreign body (FB) is underreported in the literature, but it is more commonly encountered in clinical practice. Nowadays, losing a coronary stent or a guidewire has become a rare event. However, due to the constant increase in the total number of worldwide performed coronary interventions (PCI) and especially due to an increase also in the technical difficulties of these procedures (i.e., new devices+complex techniques), this kind of "lost FB complication" may again become clinically relevant. CASE REPORTS: We report two cases where, during challenging PCIs, 0.014-in. guidewires broke, remaining firmly anchored in the coronary tree floating with their proximal part in the aorta. These wires could have been successfully retrieved with a dedicated three-dimensional snare device, which is specifically manufactured for facilitating this kind of retrieval interventions. CONCLUSIONS: Intracoronary lost guidewires, if untreated, may lead to serious cardiovascular complications, suggesting that one should attempt every possible maneuver to retrieve them from the coronary circulation. By describing the peculiarity of the Entrio snare device, we finally suggest that this kind of dedicated three-dimensional snare device is an excellent tool at cardiologists' disposal for retrieving intracardiac and intravascular lost wires.