Publications by authors named "Luca Bartolini"

36 Publications

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

Seizure 2021 Oct 31;91:150-158. Epub 2021 May 31.

Division of Neuroimmunology and Neurovirology, NINDS, NIH, Bethesda, MD, United States.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection.

Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation.

Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels.

Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.
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http://dx.doi.org/10.1016/j.seizure.2021.05.022DOI Listing
October 2021

Equipoise in Management of Patients With Acute Symptomatic Carotid Stenosis (Hot Carotid).

Neurol Clin Pract 2021 Feb;11(1):25-32

Department of Clinical Neurosciences (AG, R-JS, ASA-S, JHW, BKM), University of Calgary, Canada; Clinical Epilepsy Section (LB), National Institutes of Health, Bethesda, MD; Centre for Urban Health Solutions (DJTC), St. Michael's Hospital, Toronto, Canada; and Department of Medicine (DJTC), Department of Community Health Sciences (DJTC, BKM), Department of Radiology (JHW, BKM), and The Hotchkiss Brain Institute (JHW, BKM), University of Calgary, Canada.

Objective: To explore differences in antithrombotic management of patients with acutely symptomatic carotid stenosis ("hot carotid") awaiting revascularization with endarterectomy or stenting (CEA/CAS).

Methods: We used a worldwide electronic survey with practice-related questions and clinical questions about 3 representative scenarios. Respondents chose their preferred antithrombotic regimen (1) in general, (2) if the patient was already on aspirin, or (3) had associated intraluminal thrombus (ILT) and identified clinical/imaging factors that increased or decreased their enthusiasm for additional antithrombotic agents. Responses among different groups were compared using multivariable logistic regression.

Results: We received 668 responses from 71 countries. The majority favored CT angiography (70.2%) to evaluate carotid stenosis, CEA (69.1%) over CAS, an aspirin-containing regimen (88.5%), and a clopidogrel-containing regimen (64.4%) if already on aspirin. Whereas diverse antithrombotic regimens were chosen, monotherapy was favored by 54.4%-70.6% of respondents across 3 scenarios. The preferred dual therapy was low-dose aspirin (75-100 mg) plus clopidogrel (22.2%) or high-dose aspirin (160-325 mg) plus clopidogrel if already on aspirin (12.2%). Respondents favoring CAS more often chose ≥2 agents (adjusted odds ratio [aOR] vs CEA: 2.00, 95% confidence interval 1.36-2.95, = 0.001) or clopidogrel-containing regimens (aOR: 1.77, 1.16-2.70, = 0.008). Regional differences included respondents from Europe less commonly choosing multiple agents if already on aspirin (aOR vs United States/Canada: 0.57, 0.35-0.93, = 0.023), those from Asia more often favoring multiple agents (aOR: 1.95, 1.11-3.43, = 0.020), vs those from the United States/Canada preferentially choosing heparin-containing regimens with ILT (aOR vs rest: 3.35, 2.23-5.03, < 0.001). Factors increasing enthusiasm for ≥2 antithrombotics included multiple TIAs (57.2%), ILT (58.5%), and ulcerated plaque (57.4%); 56.3% identified MRI microbleeds as decreasing enthusiasm.

Conclusions: Our results highlight the heterogeneous management and community equipoise surrounding optimal antithrombotic regimens for hot carotids.
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http://dx.doi.org/10.1212/CPJ.0000000000000812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101303PMC
February 2021

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

Epilepsy Res 2021 May 2;172:106598. Epub 2021 Mar 2.

Center for Neuroscience, Children's National Hospital, George Washington University School of Medicine, Washington DC, USA.

Objective: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery.

Methods: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used.

Results: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm (range: 1.87-591.73 cm). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset.

Significance: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106598DOI Listing
May 2021

Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures.

J Inherit Metab Dis 2021 Jul 15;44(4):1013-1020. Epub 2021 Feb 15.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.

CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease-causing variant is an ~1-kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland-3), glutamate+glutamine+GABA and N-acetylaspartate+N-acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1-year follow-up. Seizures were reported in 14 (8 1-kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = -0.57; [-0.81,-0.17]; P = .009) and ABC (rp = -0.66; [-0.85,-0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = -0.54; [-0.80,-0.11]; P = .02) and N-acetylaspartate+N-acetylaspartyl glutamate (rp = -0.54; [-0.80,-0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings.
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http://dx.doi.org/10.1002/jimd.12366DOI Listing
July 2021

Delayed transhemispheric propagation of electrographic seizures following functional hemispherectomy.

Clin Neurol Neurosurg 2021 02 8;201:106418. Epub 2020 Dec 8.

Division of Pediatric Neurology, The Warren Alpert Medical School of Brown University, Providence, RI, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clineuro.2020.106418DOI Listing
February 2021

Teaching Video Neuroimages: Ictal Unilateral Eye Blinking in Temporal Lobe Seizures: An Illustrative Video Case.

Neurology 2021 02 14;96(7):e1094-e1095. Epub 2020 Sep 14.

From the Department of Neurology (E.R.), Rhode Island Hospital; Divisions of Pediatric Critical Care (R.M., K.M.) and Pediatric Neurology (L.B.), Hasbro Children's Hospital; and The Warren Alpert Medical School of Brown University (R.M., K.M., L.B.), Providence, RI.

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http://dx.doi.org/10.1212/WNL.0000000000010844DOI Listing
February 2021

Leading with inclusion during the COVID-19 pandemic: Stronger together.

Neurology 2020 09 14;95(12):537-542. Epub 2020 Aug 14.

From the Division of Neurology (L.W.), Cook County Health, Chicago, IL; Department of Neurology (C.Y.K.), Yale School of Medicine, New Haven, CT; Evergreen Health Neuroscience Institute (D.J.B.), Evergreen Health Medical Center, Kirkland, WA; Department of Neurology (D.J.A.), St. Luke's University Health Network, Bethlehem, PA; Rhode Island Hospital/The Warren Alpert Medical School of Brown University (L.B.), Providence; Department of Neurology (K.R.C.), Fort Belvoir Community Hospital, VA; Icahn School of Medicine at Mount Sinai (N.S.D.), New York; Division of Neurology (E.T.D.), MedStar Franklin Square Medical Center, Baltimore, MD; Department of Neurology (K.D.O.), University of Colorado, Aurora; Department of Neurology (G.L.G.P.), University of Miami-Miller School of Medicine, FL; Department of Neurology (J.K.C.-G.), Mayo Clinic, Rochester, MN; Department of Neurology (M.N.B.), Johns Hopkins School of Medicine, Baltimore, MD; San Antonio Military Medical Center (J.C.M.), TX; and University of Oxford (G.C.D.), Oxford, United Kingdom.

Inclusion is the deliberate practice of ensuring that each individual is heard, all personal traits are respected, and all can make meaningful contributions to achieve their full potential. As coronavirus disease 2019 spreads globally and across the United States, we have viewed this pandemic through the lens of equity and inclusion. Here, we discuss how this pandemic has magnified preexisting health and social disparities and will summarize why inclusion is an essential tool to traverse this uncertain terrain and discuss strategies that can be implemented at organizational and individual levels to improve inclusion and address inequities moving forward.
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http://dx.doi.org/10.1212/WNL.0000000000010641DOI Listing
September 2020

Toward clinical elastography of dermal tissues: A medical device to probe skin's elasticity through suction, with subsurface imaging via optical coherence tomography.

Rev Sci Instrum 2020 Jul;91(7):074101

Biophotonics and Medical Imaging, Department of Physics and Astronomy, Vrije Universiteit Amsterdam, De Boelelaan, 1081 HV Amsterdam, The Netherlands.

The mechanical behavior of dermal tissues is unarguably recognized for its diagnostic ability and in the last decades received a steadily increasing interest in dermatology practices. Among the various methods to investigate the mechanics of skin in clinical environments, suction-based ones are especially noteworthy, thanks to their qualities of minimal invasiveness and relative simplicity of setups and data analysis. In such experiments, structural visualization of the sample is highly desirable, both in its own right and because it enables elastography. The latter is a technique that combines the knowledge of an applied mechanical stimulus and the visualization of the induced deformation to result in a spatially resolved map of the mechanical properties, which is particularly important for an inhomogeneous and layered material such as skin. We present a device, designed for clinical trials in dermatology practices, that uses a handheld probe to (1) deliver a suction-based, controlled mechanical stimulus and (2) visualize the subsurface structure via optical coherence tomography. We also present a device-agnostic data-analysis framework, consisting of a Python library, released in the public domain. We show the working principle of the setup on a polymeric model and on a volunteer's skin.
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http://dx.doi.org/10.1063/5.0009639DOI Listing
July 2020

Worldwide survey of neurologists on approach to autoimmune encephalitis.

Neurol Clin Pract 2020 Apr;10(2):140-148

Department of Clinical Neurosciences (AG), University of Calgary, Canada; Centre for Prevention of Stroke and Dementia (AG), University of Oxford, United Kingdom; Clinical Epilepsy Section (LB), National Institutes of Health, Bethesda, MD; and Department of Neurology (SFW), Yale School of Medicine, New Haven, CT.

Objective: To explore practice differences in the diagnosis and management of autoimmune encephalitis (AE), which is complicated by issues with sensitivity/specificity of antibody testing, nonspecific MRI/EEG/CSF findings, and competing differential diagnoses.

Methods: We used a worldwide electronic survey with practice-related demographic questions and clinical questions about 2 cases: (1) a 20-year-old woman with a neuropsychiatric presentation strongly suspicious of AE and (2) a 40-year-old man with new temporal lobe seizures and cognitive impairment. Responses among different groups were compared using multivariable logistic regression.

Results: We received 1,333 responses from 94 countries; 12.0% identified as neuroimmunologists. Case 1: those treating >5 AE cases per year were more likely to send antibodies in both serum and CSF (adjusted odds ratio [aOR] vs 0 per year: 3.29, 95% CI 1.31-8.28, = 0.011), pursue empiric immunotherapy (aOR: 2.42, 95% CI 1.33-4.40, = 0.004), and continue immunotherapy despite no response and negative antibodies at 2 weeks (aOR: 1.65, 95% CI 1.02-2.69, = 0.043). Case 2: neuroimmunologists were more likely to send antibodies in both serum and CSF (aOR: 1.80, 95% CI 1.12-2.90, = 0.015). Those seeing >5 AE cases per year (aOR: 1.86, 95% CI 1.22-2.86, = 0.004) were more likely to start immunotherapy without waiting for antibody results.

Conclusions: Our results highlight the heterogeneous management of AE. Neuroimmunologists and those treating more AE cases generally take a more proactive approach to testing and immunotherapy than peers. Results highlight the need for higher-quality cohorts and trials to guide empiric immunotherapy, and evidence-based guidelines aimed at both experts and nonexperts. Because the average AE patient is unlikely to be first seen by a neuroimmunologist, ensuring greater uniformity in our approach to suspected cases is essential to ensure that patients are appropriately managed.
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http://dx.doi.org/10.1212/CPJ.0000000000000701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156195PMC
April 2020

Prevention and treatment of temporal lobe epilepsy: lessons from hepatitis B story!

Int J Neurosci 2020 Nov 27;130(11):1151-1155. Epub 2020 Feb 27.

Hasbro Children's Hospital/Alpert Medical School of Brown University, Providence, RI, USA.

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and hippocampal sclerosis (HS) is the most common pathological substrate of TLE. Considering the significant consequences of uncontrolled seizures (e.g. increased morbidity and mortality), epilepsy prevention remains a necessity that potentially could save many lives. Human herpes virus-6 (HHV-6) has been linked to TLE in humans. The relationship between HHV-6 and HS-TLE could be attributed to a neuro-inflammatory cascade triggered by the infection, involving direct neuronal damage and production of several pro-inflammatory cytokines under certain conditions that are still incompletely understood. Hepatitis B virus (HBV) infection is another chronic viral infection with a life-long latency. HBV infection is linked to various clinical conditions, including liver cirrhosis. There are currently three ways to fight HBV infection and its consequences; primary prevention (by vaccination), secondary prevention (by drug therapy), and tertiary prevention (by liver transplantation). Considering the similarities between the natural histories of HHV-6 and HBV infections, and also the successful strategies which are currently available to fight HBV infection and its long-term consequences, here, we propose three strategies to fight HHV-6 and its possible long-term consequence (i.e. HS-TLE): Primary prevention: by developing vaccines to prevent HHV-6 infection; Secondary prevention: by considering trials of antiviral drugs to treat HHV-6 infection, when it happens in the childhood to hopefully prevent its long-term consequences; and, Tertiary prevention: by stem cell therapy for drug-resistant epilepsy.
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http://dx.doi.org/10.1080/00207454.2020.1730370DOI Listing
November 2020

Differences in treatment of epilepsy in pregnancy: A worldwide survey.

Neurol Clin Pract 2019 Jun;9(3):201-207

Corinne Goldsmith Dickinson Center for Multiple Sclerosis (ICG), Mount Sinai, New York, NY; Clinical Epilepsy Section (LB), National Institute of Neurological Disorders and Stroke, Bethesda, MD; Center for Neuroscience (LB), George Washington University, Children's National Health System; Center for Healthcare Organization and Implementation Research (JN), Edith Nourse Rogers Memorial VA, Bedford, MA; and Department of Neurology (DS), University of Oklahoma.

Background: How to safely treat pregnant women with epilepsy is a question for which there are guidelines, but variations in practice exist.

Methods: To better characterize how clinicians address this difficult clinical question, we distributed an anonymous survey to neurology practitioners across subspecialties and different levels of training via the ® website. The survey was conducted from May 31 to December 3, 2017. We received responses from 642 participants representing 81 countries. We performed both descriptive and inferential analyses. For the inferential analysis, a multiple logistic regression model was used to analyze the effect of provider characteristics on the constructed binary outcome variables of interest.

Results: The results of this survey demonstrate a wide range in the amount of folic acid recommended and the frequency of checking levels of anti-epileptic drugs. Choice of first-line agent varied by the economic development status of the respondent's country, suggesting that access to medications plays an important role in clinical decision making in many parts of the world.

Conclusion: This survey highlights several areas where further research would be helpful in guiding practice.
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http://dx.doi.org/10.1212/CPJ.0000000000000642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615647PMC
June 2019

Infection with HHV-6 and its role in epilepsy.

Epilepsy Res 2019 07 29;153:34-39. Epub 2019 Mar 29.

Center for Neuroscience, Children's National Medical Center, George Washington University, 111 Michigan Ave NW, Washington, DC 20010, USA.

Infection with Human Herpesvirus-6 (HHV-6) has been associated with different epilepsy syndromes, including febrile seizures and status epilepticus, acute symptomatic seizures secondary to encephalitis and temporal lobe epilepsy. This neurotropic DNA virus is ubiquitous and primary infection occurs in up to 80% of children by age two years. While two viral variants have been identified, HHV-6B is the one that has been primarily linked to disease in humans, including epilepsy. After initial viremia, the virus can establish chronic latency in brain tissue, peripherally in tonsils and salivary glands and infect several different cell lines by binding to the complement regulator CD-46. In this review we will focus on discussing the evidence linking HHV-6 infection to different epilepsy syndromes and analyzing proposed pathogenic mechanisms.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.03.016DOI Listing
July 2019

Detection of HHV-6 and EBV and Cytokine Levels in Saliva From Children With Seizures: Results of a Multi-Center Cross-Sectional Study.

Front Neurol 2018 5;9:834. Epub 2018 Oct 5.

Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States.

One third of children with epilepsy are refractory to medications. Growing data support a role of common childhood infections with neurotropic viruses and inflammation in epileptogenesis. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures. In this cross-sectional multi-center study, we collected saliva from 115 consecutive children with acute seizures (cases), 51 children with a fever and no seizures or underlying neurological disease (fever controls) and 46 healthy children (healthy controls). Specimens were analyzed by a novel droplet digital PCR for HHV-6 and EBV viral DNA and a bead-based immunoassay for neuroinflammatory cytokines. Cases included febrile seizures ( = 30), acute seizures without ( = 53) and with fever ( = 4) in chronic epilepsy, new onset epilepsy ( = 13), febrile status epilepticus ( = 3), and first lifetime seizure ( = 12). HHV-6 DNA was found in 40% of cases vs. 37% fever controls and 35% healthy controls, with no statistically significant differences. EBV DNA was also detected with no differences in 17% cases, 16% fever controls, and 28% healthy controls. IL-8 and IL-1β were increased in saliva of 32 random samples from cases compared with 30 fever controls: IL-8 cases mean (SD): 1158.07 pg/mL (1427.41); controls 604.92 (754.04); = 0.02. IL-1β 185.76 (230.57); controls 86.99 (187.39); = 0.0002. IL-1β level correlated with HHV6 viral load ( = 0.007). Increase in inflammatory cytokines may play a role in the onset of acute seizures and saliva could represent an inexpensive and non-invasive method for detection of viral DNA and cytokines.
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http://dx.doi.org/10.3389/fneur.2018.00834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182262PMC
October 2018

Comparison of frequency and strain-rate domain mechanical characterization.

Sci Rep 2018 09 12;8(1):13697. Epub 2018 Sep 12.

Biophotonics & Medical Imaging and LaserLaB, Vrije Universiteit Amsterdam, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.

Indentation is becoming increasingly popular to test soft tissues and (bio)materials. Each material exhibits an unknown intrinsic "mechanical behaviour". However, limited consensus on its "mechanical properties" (i.e. quantitative descriptors of mechanical behaviour) is generally present in the literature due to a number of factors, which include sample preparation, testing method and analysis model chosen. Viscoelastic characterisation - critical in applications subjected to dynamic loading conditions - can be performed in either the time- or frequency-domain. It is thus important to selectively investigate whether the testing domain affects the mechanical results or not. We recently presented an optomechanical indentation tool which enables both strain-rate (nano-[Formula: see text]) and frequency domain (DMA) measurements while keeping the sample under the same physical conditions and eliminating any other variability factor. In this study, a poly(dimethylsiloxane) sample was characterised with our system. The DMA data were inverted to the time-domain through integral transformations and then directly related to nano-[Formula: see text] strain-rate dependent results, showing that, even though the data do not perfectly overlap, there is an excellent correlation between them. This approach indicates that one can convert an oscillatory measurement into a strain-rate one and still capture the trend of the "mechanical behaviour" of the sample investigated.
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http://dx.doi.org/10.1038/s41598-018-31737-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135832PMC
September 2018

Fueling the FIRES: Hemophagocytic lymphohistiocytosis in febrile infection-related epilepsy syndrome.

Epilepsia 2018 09 22;59(9):1753-1763. Epub 2018 Aug 22.

Departments of Neurology and Immunology, Center for MS and Autoimmune Neurology, Translational Neuroimmunology Lab, Mayo Clinic, Rochester, Minnesota.

Objectives: Although secondary hemophagocytic lymphohistiocytosis (HLH) has been reported in children with critical illness of various etiologies, it has not been reported in patients with febrile infection-related epilepsy syndrome (FIRES). We describe a series of patients with concurrent HLH and FIRES in an effort to establish common pathophysiologic abnormalities.

Methods: Five patients with FIRES who were assessed for HLH were identified from a neurocritical care database. All were previously healthy and had extensive diagnostic testing. All had clinical deterioration with multiorgan dysfunction prompting HLH screening 20-29 days after hospitalization. Markers for inflammatory dysregulation were assessed in cerebrospinal fluid (CSF) and serum at various time points. Outcomes were assessed 6 months after presentation.

Results: Three patients met clinical criteria for secondary HLH. Elevation of specific cytokines/chemokines was variable. CSF neopterin, high mobility group box 1 (HMGB1), and C-X-C motif chemokine ligand 8 (CXCL8) were significantly elevated in all. Interleukin-1β (IL-1β) and IL-18 were not elevated in any of the samples. Treatment and outcomes were variable.

Significance: We describe 3 patients with HLH and FIRES. The co-occurrence of these 2 rare disorders suggests the possibility of a common immune dysregulation phenotype prolonging epileptogenesis. HLH screening in critically ill patients with FIRES may yield a broader understanding of shared inflammatory processes.
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http://dx.doi.org/10.1111/epi.14524DOI Listing
September 2018

Viral Triggers and Inflammatory Mechanisms in Pediatric Epilepsy.

Mol Neurobiol 2019 Mar 5;56(3):1897-1907. Epub 2018 Jul 5.

Center for Neuroscience, Children's National Medical Center, George Washington University, 111 Michigan Ave NW, Washington, DC, 20010, USA.

Experimental and clinical findings suggest a crucial role for inflammation in the onset of pediatric seizures; this mechanism is not targeted by conventional antiepileptic drugs and may contribute to refractory epilepsy. Several triggers, including infection with neurotropic viruses such as human herpesvirus 6 (HHV-6), other herpesviruses, and picornaviruses, appear to induce activation of the innate and adaptive immune systems, which results in several neuroinflammatory responses, leading to enhanced neuronal excitability, and ultimately contributing to epileptogenesis. This review discusses the proposed mechanisms by which infection with herpesviruses, and particularly with HHV-6, and ensuing inflammation may lead to seizure generation, and later development of epilepsy. We also examine the evidence that links herpesvirus and picornavirus infections with acute seizures and chronic forms of epilepsy. Understanding the mechanisms by which specific viruses may trigger a cascade of alterations in the CNS ultimately leading to epilepsy appears critical for the development of therapeutic agents that may target the virus or inflammatory mechanisms early and prevent progression of epileptogenesis.
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http://dx.doi.org/10.1007/s12035-018-1215-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416551PMC
March 2019

Uncertainties from a worldwide survey on antiepileptic drug withdrawal after seizure remission.

Neurol Clin Pract 2018 Apr;8(2):108-115

Clinical Epilepsy Section (LB) and Stroke Diagnostics and Therapeutics Section (SM), National Institute of Neurological Disorders and Stroke, Bethesda, MD; Center for Neuroscience (LB), George Washington University, Children's National Health System; and Department of Neurology (SM, MZK), George Washington University Hospital, Washington, DC.

Background: We sought to determine differences in practice for discontinuation of antiepileptic drugs (AEDs) after seizure remission and stimulate the planning and conduction of withdrawal trials.

Methods: We utilized a worldwide electronic survey that included questions about AED discontinuation for 3 paradigmatic cases in remission: (1) focal epilepsy of unknown etiology, (2) temporal lobe epilepsy after surgery, and (3) juvenile myoclonic epilepsy. We analyzed 466 complete questionnaires from 53 countries, including the United States. Statistical analysis included χ and multivariate logistic regression.

Results: Case 1: responders in practice for <10 years were less likely to taper AEDs: odds ratio (OR) (95% confidence interval [CI]) 0.52 (0.32-0.85), = 0.02. The likelihood of stopping AEDs was higher among doctors treating children: OR (95% CI): 11.41 (2.51-40.13), = 0.002. Doctors treating children were also more likely to stop after 2 years or less of remission: OR (95% CI): 6.91 (2.62-19.31), = 0.002, and the same was observed for US physicians: OR (95% CI): 1.61 (1.01-2.57), = 0.0049. Case 2: responders treating children were more likely to taper after 1 year or less of postoperative remission, with the goal of discontinuing all medications: OR (95% CI): 1.91 (1.09-3.12), = 0.015, and so were US-based responders: OR (95% CI): 1.73 (1.21-2.41), = 0.003. Case 3: epileptologists were less likely to withdraw the medication: OR (95% CI): 0.56 (0.39-0.82), = 0.003, and so were those in practice for 10 or more years: OR (95% CI): 0.54 (0.31-0.95), = 0.025.

Conclusions: We observed several differences in practice for AED withdrawal after seizure remission that highlight global uncertainty. Trials of AED discontinuation are needed to provide evidence-based guidance.
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http://dx.doi.org/10.1212/CPJ.0000000000000441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914742PMC
April 2018

"Curious George Goes to the Hospital": teaching toddlers how good healthcare works.

Authors:
Luca Bartolini

BMJ 2018 02 6;360:k487. Epub 2018 Feb 6.

Clinical Epilepsy Section and Division of Neuroimmunology and Neurovirology, National Institutes of Health, 10 Center Drive, Bethesda, MD 20814-1408, USA.

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http://dx.doi.org/10.1136/bmj.k487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889974PMC
February 2018

Transient postictal blindness after a focal posterior cingulate gyrus seizure.

Seizure 2018 01 17;54:58-60. Epub 2017 Dec 17.

Electroencephalography Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

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http://dx.doi.org/10.1016/j.seizure.2017.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364341PMC
January 2018

Early ictal and interictal patterns in FIRES: The sparks before the blaze.

Epilepsia 2017 08 26;58(8):1340-1348. Epub 2017 May 26.

Center for Neuroscience, Children's National Health System, George Washington University, Washington, District of Columbia, U.S.A.

Objective: Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy described as explosive onset of super refractory status epilepticus (SRSE) in previously healthy children. We describe electroencephalography (EEG) abnormalities in the hyperacute phase of FIRES, with the aim of contributing to the diagnostic characterization of a syndrome otherwise lacking specific biomarkers.

Methods: This is a retrospective single-center, case series of seven children with FIRES. Cases were identified from a Neurocritical Care database. Patient characteristics and clinical course were obtained from electronic medical records. Electroencephalography recordings were reviewed in two segments: the initial 12 h of recording and the 12 h prior to initiation of a medically induced burst suppression (BS).

Results: Fourteen 12-h segments of video-electroencephalography (EEG) recordings were analyzed for commonalities. A beta-delta complex resembling extreme delta brush (EDB) occurred in at least one 12-h segment for all patients. In six patients, seizures were brief and relatively infrequent during the first recording, with a gradual evolution to status epilepticus by the second. We observed a characteristic electrographic seizure pattern in six of seven patients with prolonged focal fast activity at onset. Shifting seizures were seen in four of seven patients.

Significance: The diagnosis of FIRES is typically assigned late in a patient's clinical course, which has broad implications for clinical care and research. We retrospectively analyzed acute EEG features in seven patients with FIRES and discovered three common features: gradual increase in seizure burden, presence of a recurrent EDB, and a typical seizure pattern. Recognition of this pattern may facilitate early diagnosis and treatment.
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http://dx.doi.org/10.1111/epi.13801DOI Listing
August 2017

Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey.

J Neurol 2017 Apr 2;264(4):647-653. Epub 2017 Feb 2.

Department of Pediatrics, Sections of Immunology, Allergy and Rheumatology and Co-appointment in Child Neurology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.

The objective of the study was to identify differences in treatment strategies for anti-NMDA receptor encephalitis based on specialty of treating physicians, geographic location, and years in practice. We conducted an anonymous worldwide electronic survey through the Practice Current section of Neurology Clinical Practice to appraise differences in decisions about first- and second-line treatment and timing for initiation of second-line treatment for anti-NMDA receptor encephalitis. 399 participants answered all questions of the survey and were included in the analysis. 261 (65%) were adult neurologists, 86 (22%) were neurologists treating children, and 52 (13%) were pediatric rheumatologists. 179 (45%) responders practiced in the US. The majority agreed on the use of steroids and/or IVIg for first-line therapy and rituximab alone as second line. Differences in initial treatment regimen based on specialty included increased use of plasma exchange by adult neurologists (27%) and rituximab by pediatric rheumatologists (29%) (χ (4) = 27.43, p < 0.001). Trainees opted for plasma exchange (35%) and junior faculty picked rituximab (15%) more as part of first line (χ (4) = 13.37, p = 0.010). There was greater usage of anti-metabolites for second-line therapy outside of the US (15%) (χ (4) = 11.67, p = 0.020). US physicians also utilized second-line treatment earlier than their mostly European counterparts (14 vs. 23% used later than 2 weeks; χ (1) = 4.96, p = 0.026). Although treatment patterns were similar, differences observed across specialties and geographic locations may guide the development of consensus-driven guidelines by multi-disciplinary task forces. These guidelines may promote treatment trials of immunomodulators in autoimmune encephalitides.
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http://dx.doi.org/10.1007/s00415-017-8407-1DOI Listing
April 2017

Teaching NeuroImages: Homotopic motor distribution on fMRI in closed-lip schizencephaly.

Neurology 2017 01;88(2):e24-e25

From the Center for Neuroscience and Behavioral Medicine (L.B., A.K., A.Z., W.D.G.) and the Division of Diagnostic Imaging and Radiology (J.G.M.), Children's National Health System, The George Washington University, Washington, DC.

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http://dx.doi.org/10.1212/WNL.0000000000003493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224712PMC
January 2017

Practice Current: Establishing worldwide connections.

Authors:
Luca Bartolini

Neurol Clin Pract 2016 Dec;6(6):470-471

Department of Neurology, Children's National Health System, Washington, DC.

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http://dx.doi.org/10.1212/CPJ.0000000000000317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964815PMC
December 2016

Temporal lobe epilepsy and focal cortical dysplasia in children: A tip to find the abnormality.

Epilepsia 2017 01 16;58(1):113-122. Epub 2016 Nov 16.

Center for Neuroscience, Children's National Health System, George Washington University, Washington, District of Columbia, U.S.A.

Objective: To demonstrate an association between magnetic resonance imaging (MRI) findings and pathologic characteristics in children who had surgery for medically refractory epilepsy due to focal cortical dysplasia (FCD).

Methods: We retrospectively studied 110 children who had epilepsy surgery. Twenty-seven patients with FCD were included. Thirteen had temporal lobe epilepsy (TLE) and 14 had extra-temporal lobe epilepsy (ETLE). Three patients had associated mesial temporal sclerosis. Preoperative 3T MRIs interleaved with nine controls were blindly re-reviewed and categorized according to signal alteration. Pathologic specimens were classified according to the 2011 International League Against Epilepsy (ILAE) classification and compared to MRI studies.

Results: Rates of pathology subtypes differed between TLE and ETLE (χ (3) = 8.57, p = 0.04). FCD type I was more frequent in TLE, whereas FCD type II was more frequent in ETLE. In the TLE group, nine patients had temporal tip abnormalities. They all exhibited gray-white matter blurring with decreased myelination and white matter hyperintense signal. Blurring involved the whole temporal tip, not just the area of dysplasia. These patients were less likely to demonstrate cortical thickening compared to those without temporal tip findings (χ (1) = 9.55, p = 0.002). Three of them had FCD Ib, three had FCD IIa, two had FCD IIIa, and one had FCD IIb; MRI features could not entirely distinguish between FCD subtypes. TLE patients showed more pronounced findings than ETLE on MRI (χ (1) = 11.95, p = 0.003, odds ratio [OR] 18.00). In all cases of FCD, isolated blurring was more likely to be associated with FCD II, whereas blurring with decreased myelination was seen with FCD I (χ (6) = 13.07, p = 0.042).

Significance: Our study described associations between MRI characteristics and pathology in children with FCD and offered a detailed analysis of temporal lobe tip abnormalities and FCD subtypes in children with TLE. These findings may contribute to the presurgical evaluation of patients with refractory epilepsy.
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http://dx.doi.org/10.1111/epi.13615DOI Listing
January 2017

A Practical Approach to Ketogenic Diet in the Pediatric Intensive Care Unit for Super-Refractory Status Epilepticus.

Neurocrit Care 2017 04;26(2):267-272

Department of Child Neurology, Pediatric Neurocritical Care, Children's National Health System, 111 Michigan Avenue NW, Washington DC, 20010, USA.

Background: Super-refractory status epilepticus (SRSE) ensues when there is no improvement of seizure control in response to anesthetic therapy or seizure recurrence after reduction of anesthetic agents. There is no consensus on standard of care for SRSE. Ketogenic diet (KD) has reported success, but technical challenges exist including inability to feed patients, concomitant steroid use, acidotic states, and lack of dieticians with experience. The optimal protocol for KD is yet to be determined. We describe our approach to initiation of KD in the pediatric intensive care unit (PICU).

Methods: Patients with SRSE who had KD initiation in the PICU were identified. Data from the hospital course were supplemented by review of the electronic medical record.

Results: Nine children with SRSE who had KD initiated in the PICU were identified. Descriptive analysis was performed. Mean age was 5.4 years (SD 2.24). Median number of days to start KD from detection of seizures was 13 [interquartile range (IQR) 10-16]. Mean time to achieve ketosis was 4.2 days (SD 3.4). The median number of antiepileptic drugs (AEDs) trialed before KD was started was 4 [IQR 3-4], and the median number of continuous infusions was 2 [IQR 2-3]. After initiation of KD, most patients were weaned off anesthetic infusions by 1 week. Outcomes were variable.

Conclusions: We demonstrated the feasibility of a practical approach to initiation of KD for children with SRSE. These children were successfully weaned off continuous anesthetic infusions. Larger studies are needed to determine effectiveness, safety, and tolerability of KD in the management of SRSE as well as ease of implementation.
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http://dx.doi.org/10.1007/s12028-016-0312-4DOI Listing
April 2017

Practice Current: What is your diagnostic evaluation of cryptogenic stroke?

Authors:
Luca Bartolini

Neurol Clin Pract 2016 Jun;6(3):271-276

Department of Neurology, Children's National Health System, Washington, DC.

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http://dx.doi.org/10.1212/CPJ.0000000000000255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727713PMC
June 2016

Practice Current: A new way of interpreting contemporary neurology.

Neurol Clin Pract 2016 Feb;6(1):14-15

Department of Neurology (LB), Children's National Health System, Washington, DC; and Epilepsy Center (JJM), Ann & Robert H. Lurie Children's Hospital of Chicago, Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1212/CPJ.0000000000000216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765892PMC
February 2016
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