Publications by authors named "Marta Amengual-Gual"

21 Publications

  • Page 1 of 1

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

Epilepsia 2021 Jul 12. Epub 2021 Jul 12.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE.

Methods: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients.

Results: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion.

Significance: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.
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http://dx.doi.org/10.1111/epi.16984DOI Listing
July 2021

Convolutional neural networks to identify malformations of cortical development: A feasibility study.

Seizure 2021 May 31;91:81-90. Epub 2021 May 31.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA USA.

Objective: To develop and test a deep learning model to automatically detect malformations of cortical development (MCD).

Methods: We trained a deep learning model to distinguish between diffuse cortical malformation (CM), periventricular nodular heterotopia (PVNH), and normal magnetic resonance imaging (MRI). We trained 4 different convolutional neural network (CNN) architectures. We used batch normalization, global average pooling, dropout layers, transfer learning, and data augmentation to minimize overfitting.

Results: There were 45 subjects (866 images) with a normal MRI, 52 subjects (790 images) with CM, and 32 subjects (750 images) with PVNH. There was no subject overlap between the training, validation, and test sets. The InceptionResNetV2 architecture performed best in the validation set in all models and was evaluated in the test set with the following results: 1) the model distinguishing between CM and normal MRI yielded an area under the curve (AUC) of 0.89 and accuracy of 0.81; 2) the model distinguishing between PVNH and normal MRI yielded an AUC of 0.90 and accuracy of 0.84; 3) the model distinguishing between the three classes (CM, PVNH, and normal MRI) yielded an AUC of 0.88 and accuracy of 0.74. Visualization with gradient-weighted class activation maps and saliency maps showed that the deep learning models classified images based on relevant areas within each image.

Significance: This study showed that CNNs can detect MCD at a clinically useful performance level with a fully automated workflow without image feature selection.
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http://dx.doi.org/10.1016/j.seizure.2021.05.023DOI Listing
May 2021

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

Pediatr Crit Care Med 2021 Jun 14. Epub 2021 Jun 14.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA. Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, MN. Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI. Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Barcelona, Spain. Division of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain. Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX. Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH. Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, VA. Center for Neuroscience, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC. Departments of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, IL. Division of Pediatric Neurology, Washington University Medical Center, Washington University School of Medicine, Saint Louis, MO. Section of Pediatric Critical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, TX. Division of Child Neurology, Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY. Division of Pediatric Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, NC. Department of Neurology, Division of Pediatric Neurology, University of Washington, Seattle, WA. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA. Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University. Columbus, OH. Department of Pediatrics, Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland, OR. Division of Critical Care, Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA. Critical Care and Pediatrics, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Department of Child Health, University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital, Phoenix, AZ.

Objectives: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients.

Design: Retrospective cohort study with prospectively collected data between June 2011 and January 2019.

Setting: Seventeen academic hospitals in the United States.

Patients: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups.

Interventions: None.

Measurements And Main Results: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments.

Conclusions: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.
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http://dx.doi.org/10.1097/PCC.0000000000002786DOI Listing
June 2021

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

Epilepsia 2021 Jul 6;62(7):1629-1642. Epub 2021 Jun 6.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE).

Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever.

Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function.

Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.
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http://dx.doi.org/10.1111/epi.16950DOI Listing
July 2021

Time to Treatment in Pediatric Convulsive Refractory Status Epilepticus: The Weekend Effect.

Pediatr Neurol 2021 Jul 26;120:71-79. Epub 2021 Mar 26.

Department of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency.

Methods: We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus.

Results: We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01).

Conclusions: The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.03.009DOI Listing
July 2021

Descriptive epidemiology and health resource utilization for status epilepticus in the emergency department in the United States of America.

Seizure 2021 Apr 16;87:7-16. Epub 2021 Feb 16.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Instituto de Pediatría, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Servicio de Neuropsiquiatría Infantil. Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago, Chile.

Objective: To describe the epidemiology and health resource utilization for convulsive status epilepticus (SE) in the emergency department (ED).

Methods: Retrospective descriptive study in the Nationwide Emergency Department Sample (NEDS). Primary SE and secondary SE (SE in a case who visited the ED for other primary reason) were compared with non-SE seizures. Secondary SE is expected to have worse outcomes and higher costs because of another primary cause for ED visit.

Results: In the period 2010-2014, there were 149,750 ED visits with primary SE; 83,459 ED with secondary SE; and 5,359,103 ED visits with non-SE seizures. On multivariable analysis adjusting for potential confounders, the odds of hospital admission were 7 times higher for primary SE than for non-SE seizures, and 5 times higher for secondary SE than for non-SE seizures; the odds of transfer to another hospital were 9 times higher for primary SE than for non-SE seizures, and 3 times higher for secondary SE than for non-SE seizures; the odds of death were 2.5 times higher for primary SE than for non-SE seizures, and 12 times higher for secondary SE than for non-SE seizures; and the charges (in January 2020 USA dollars) were $9000 higher in primary SE than in non-SE seizures, and $35,000 higher in secondary SE than in non-SE seizures.

Conclusion: Among all reasons for ED visits, SE, and in particular, secondary SE, are among the most resource-consuming conditions, being much more expensive than non-SE seizures in the ED.
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http://dx.doi.org/10.1016/j.seizure.2021.02.020DOI Listing
April 2021

Twenty-four-hour patterns in electrodermal activity recordings of patients with and without epileptic seizures.

Epilepsia 2021 Apr 23;62(4):960-972. Epub 2021 Feb 23.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Daytime and nighttime patterns affect the dynamic modulation of brain and body functions and influence the autonomic nervous system response to seizures. Therefore, we aimed to evaluate 24-hour patterns of electrodermal activity (EDA) in patients with and without seizures.

Methods: We included pediatric patients with (a) seizures (SZ), including focal impaired awareness seizures (FIAS) or generalized tonic-clonic seizures (GTCS), (b) no seizures and normal electroencephalography (NEEG), or (c) no seizures but epileptiform activity in the EEG (EA) during vEEG monitoring. Patients wore a device that continuously recorded EDA and temperature (TEMP). EDA levels, EDA spectral power, and TEMP levels were analyzed. To investigate 24-hour patterns, we performed a nonlinear mixed-effects model analysis. Relative mean pre-ictal (-30 min to seizure onset) and post-ictal (I: 30 min after seizure offset; II: 30 to 60 min after seizure offset) values were compared for SZ subgroups.

Results: We included 119 patients (40 SZ, 17 NEEG, 62 EA). EDA level and power group-specific models (SZ, NEEG, EA) (h = 1; P < .01) were superior to the all-patient cohort model. Fifty-nine seizures were analyzed. Pre-ictal EDA values were lower than respective 24-hour modulated SZ group values. Post hoc comparisons following the period-by-seizure type interaction (EDA level:  = 18.50; P < .001, and power:  = 6.73; P = .035) revealed that EDA levels were higher in the post-ictal period I for FIAS and GTCS and in post-ictal period II for GTCS only compared to the pre-ictal period.

Significance: Continuously monitored EDA shows a pattern of change over 24 hours. Curve amplitudes in patients with recorded seizures were lower as compared to patients who did not exhibit seizures during the recording period. Sympathetic skin responses were greater and more prolonged in GTCS compared to FIAS. EDA recordings from wearable devices offer a noninvasive tool to continuously monitor sympathetic activity with potential applications for seizure detection, prediction, and potentially sudden unexpected death in epilepsy (SUDEP) risk estimation.
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http://dx.doi.org/10.1111/epi.16843DOI Listing
April 2021

Cost-effectiveness of adrenocorticotropic hormone versus oral steroids for infantile spasms.

Epilepsia 2021 02 8;62(2):347-357. Epub 2021 Jan 8.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective: To compare the effectiveness and cost-effectiveness of adrenocorticotropic hormone (ACTH) and oral steroids as first-line treatment for infantile spasm resolution, we performed a systematic review, meta-analysis, and cost-effectiveness study.

Methods: A decision analysis model was populated with effectiveness data from a systematic review and meta-analysis of existing literature and cost data from publicly available prices. Effectiveness was defined as the probability of clinical spasm resolution 14 days after treatment initiation.

Results: We included 21 studies with a total of 968 patients. The effectiveness of ACTH was not statistically significantly different from that of oral steroids (.70, 95% confidence interval [CI] = .60-.79 vs. .63, 95% CI = .56-.70; p = .28). Considering only the three available randomized trials with a total of 185 patients, the odds ratio of spasm resolution at 14 days with ACTH compared to high-dose prednisolone (4-8 mg/kg/day) was .92 (95% CI = .34-2.52, p = .87). Adjusting for potential publication bias, estimates became even more favorable to high-dose prednisolone. Using US prices, the more cost-effective treatment was high-dose prednisolone, with an incremental cost-effectiveness ratio (ICER) of $333 per case of spasms resolved, followed by ACTH, with an ICER of $1 432 200 per case of spasms resolved. These results were robust to multiple sensitivity analyses and different assumptions. Prednisolone at 4-8 mg/kg/day was more cost-effective than ACTH under a wide range of assumptions.

Significance: For infantile spasm resolution 2 weeks after treatment initiation, current evidence does not support the preeminence of ACTH in terms of effectiveness and, especially, cost-effectiveness.
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http://dx.doi.org/10.1111/epi.16799DOI Listing
February 2021

The burden of decisional uncertainty in the treatment of status epilepticus.

Epilepsia 2020 10 22;61(10):2150-2162. Epub 2020 Sep 22.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Treatments for convulsive status epilepticus (SE) have a wide range of effectiveness. The estimated effectiveness of non-intravenous benzodiazepines (non-IV BZDs) ranges from approximately 70% to 90% and the estimated effectiveness of non-benzodiazepine antiseizure medications (non-BZD ASMs) ranges from approximately 50% to 80%. This study aimed to quantify the clinical and economic burden of decisional uncertainty in the treatment of SE.

Methods: We performed a decision analysis that evaluates how decisional uncertainty on treatment choices for SE impacts hospital admissions, intensive care unit (ICU) admissions, and costs in the United States. We evaluated treatment effectiveness based on the available literature.

Results: Use of a non-IV BZD with high estimated effectiveness, like intranasal midazolam, rather than one with low estimated effectiveness, like rectal diazepam, would result in a median (p -p ) reduction in hospital admissions from 6 (3.9-8.8) to 1.1 (0.7-1.8) per 100 cases and associated cost reductions of $638 ($289-$1064) per pediatric patient and $1107 ($972-$1281) per adult patient. For BZD-resistant SE, use of a non-BZD ASM with high estimated effectiveness, like phenobarbital, rather than one with low estimated effectiveness, like phenytoin/fosphenytoin, would result in a reduction in ICU admissions from 9.1 (7.3-11.2) to 3.9 (2.6-5.5) per 100 cases and associated cost reduction of $1261 ($445-$2223) per pediatric patient and $319 ($-93-$806) per adult patient. Sensitivity analyses showed that relatively minor improvements in effectiveness may lead to substantial reductions in downstream hospital admissions, ICU admissions, and costs.

Significance: Decreasing decisional uncertainty and using the most effective treatments for SE may substantially decrease hospital admissions, ICU admissions, and costs.
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http://dx.doi.org/10.1111/epi.16646DOI Listing
October 2020

First-line medication dosing in pediatric refractory status epilepticus.

Neurology 2020 11 10;95(19):e2683-e2696. Epub 2020 Sep 10.

From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.

Objective: To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.

Methods: This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.

Results: We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95).

Conclusion: BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.

Classification Of Evidence: This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.
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http://dx.doi.org/10.1212/WNL.0000000000010828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713738PMC
November 2020

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

Epilepsy Curr 2020 Sep 21;20(5):245-264. Epub 2020 Aug 21.

2948Drake University, Des Moines, IA, USA.

Purpose: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE.

Methods: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process.

Results: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study).

Conclusions: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.
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http://dx.doi.org/10.1177/1535759720928269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576920PMC
September 2020

Retrospective observational study on hospital readmission for status epilepticus in the United States over 2016.

Epilepsia 2020 07 19;61(7):1386-1396. Epub 2020 Jul 19.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Objective: Describe hospital readmission for status epilepticus (SE) in the United States, and study potential risk factors for readmission.

Methods: This is a retrospective observational study using the Healthcare Cost and Utilization Project's 2016 Nationwide Readmissions Database. We studied patients of all ages admitted to the hospital due to SE.

Results: We included 32 327  patients admitted for SE in 2016. 8.4% of these patients were readmitted for SE at least one more time within 2016 (cross-sectional analysis). The incidence rate was 18 readmissions for SE per 1000 patient-months. Among the survivors of the index admission for SE who had at least 6 months of follow-up within this database (16 043  patients), the cumulative probability of having a readmission for SE at 1, 3, and 6 months from the index admission was approximately 3.5%, 7.5%, and 11%, respectively (time-to-event analysis). Patients with refractory epilepsy were more likely to have a readmission for SE compared to patients without refractory epilepsy (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.23-1.82, adjusted P =.0006), and pediatric patients were more likely to have a readmission for SE compared to adult patients (HR 1.53, 95% CI 1.26-1.87, adjusted P = .0003) during 6-month follow-up.

Significance: Hospital readmissions for SE in the United States are frequent. Independent factors associated with readmission in this database were refractory epilepsy and pediatric age.
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http://dx.doi.org/10.1111/epi.16586DOI Listing
July 2020

Association of guideline publication and delays to treatment in pediatric status epilepticus.

Neurology 2020 09 1;95(9):e1222-e1235. Epub 2020 Jul 1.

From the Division of Epilepsy and Clinical Neurophysiology (I.S.F., M.A.-G., C.B.A., J.C., M.G.-L., A.V., T.L.), Department of Neurology, and Department of Neurology (R.C.T.), Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Department of Child Neurology (I.S.F.), Hospital Sant Joan de Déu, Universitat de Barcelona, Spain; Division of Neurology (N.S.A.), Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Pediatric Critical Care Medicine (A.A., Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH; University of Virginia Health (J.N.B., H.P.G.), Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.E.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Pediatric Neurology (R.F.-M., K.S.), Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Instituto de Pediatría (M.G.-L.), Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.G., T.M.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric and Developmental Neurology (R.M.G.), Department of Neurology, Washington University School of Medicine, St. Louis, MO; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Pediatrics and Neurology (L.A.M., E.N., M.S.W.), Seattle Children's Hospital, University of Washington; Center for Integrative Brain Research (L.A.M., E.N., M.S.W.), Seattle Children's Research Institute, WA; Department of Neurology (E.P.), Mayo Clinic, Mayo Clinic School of Medicine, Rochester, MN; Department of Neurology (J.P.), Doernbercher Children's Hospital, Oregon Health & Science University, Portland; Department of Neurology (A.O.), Nationwide Children's Hospital, Ohio State University, Columbus; Division of Child Neurology and Institute for Genomic Medicine (T.T.S.), Columbia University Irving Medical Center, New York Presbyterian Hospital, New York; Division of Critical Care Medicine (A.A.T.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Division of Child and Adolescent Neurology (A.V.), Department of Neurology, Mayo Clinic, Rochester, MN; Barrow Neurological Institute (A.W., K.W.), Phoenix Children's Hospital; and Department of Pediatrics (A.W., K.W.), University of Arizona School of Medicine, Phoenix.

Objective: To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review.

Methods: We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE.

Results: We studied 328 patients (56% male) with median (25th-75th percentile [p-p]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p-p) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes, = 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes, = 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes, = 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%], = 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3], = 0.0005).

Conclusion: Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival.
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http://dx.doi.org/10.1212/WNL.0000000000010174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538224PMC
September 2020

Deep learning in rare disease. Detection of tubers in tuberous sclerosis complex.

PLoS One 2020 29;15(4):e0232376. Epub 2020 Apr 29.

Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.

Objective: To develop and test a deep learning algorithm to automatically detect cortical tubers in magnetic resonance imaging (MRI), to explore the utility of deep learning in rare disorders with limited data, and to generate an open-access deep learning standalone application.

Methods: T2 and FLAIR axial images with and without tubers were extracted from MRIs of patients with tuberous sclerosis complex (TSC) and controls, respectively. We trained three different convolutional neural network (CNN) architectures on a training dataset and selected the one with the lowest binary cross-entropy loss in the validation dataset, which was evaluated on the testing dataset. We visualized image regions most relevant for classification with gradient-weighted class activation maps (Grad-CAM) and saliency maps.

Results: 114 patients with TSC and 114 controls were divided into a training set, a validation set, and a testing set. The InceptionV3 CNN architecture performed best in the validation set and was evaluated in the testing set with the following results: sensitivity: 0.95, specificity: 0.95, positive predictive value: 0.94, negative predictive value: 0.95, F1-score: 0.95, accuracy: 0.95, and area under the curve: 0.99. Grad-CAM and saliency maps showed that tubers resided in regions most relevant for image classification within each image. A stand-alone trained deep learning App was able to classify images using local computers with various operating systems.

Conclusion: This study shows that deep learning algorithms are able to detect tubers in selected MRI images, and deep learning can be prudently applied clinically to manually selected data in a rare neurological disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190137PMC
July 2020

Estimating the cost of status epilepticus admissions in the United States of America using ICD-10 codes.

Seizure 2019 Oct 4;71:295-303. Epub 2019 Sep 4.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Estimate the cost of status epilepticus (SE) admissions in the USA using claim databases based on ICD-10 codes.

Method: Descriptive retrospective study using national estimates for the year 2016 from the KID's Inpatient Database (KID) for pediatric patients and from the National Inpatient Sample (NIS) for adults. These databases are comprehensive collections of all-payer, encounter-level hospital care data in the United States of America.

Results: From a population of 6,106,405 pediatric admissions there were 580 admissions related to SE. From a population of 29,274,158 adult admissions there were 1,405 admissions related to SE. The median (p25-p75) cost of pediatric admissions related to SE was $8,749 ($4,875-$19,067) in 2016 USA dollars [$9,295 ($5,180-$20,258) in inflation-adjusted 2019 USA dollars], and for adult admissions related to SE it was $14,678 ($7,203-$28,388) in 2016 USA dollars [$15,595 ($7,653-$30,161) in inflation-adjusted 2019 USA dollars]. Transforming to 2019 USA dollars, the values from the current study are consistent with prior estimates in the literature from the KID and NIS databases with a progressive increase, except for the cost of super-refractory SE in children that has increased disproportionately.

Conclusions: This study estimates that the cost of admissions related to SE in the USA is approximately $9,000 in children and $15,000 in adults and shows that the cost estimates have not markedly changed with the advent of ICD-10.
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http://dx.doi.org/10.1016/j.seizure.2019.09.001DOI Listing
October 2019

The onset of pediatric refractory status epilepticus is not distributed uniformly during the day.

Seizure 2019 Aug 18;70:90-96. Epub 2019 Jun 18.

Department of Neurology, Doernbercher Children's Hospital, Oregon Health & Science University, Portland, OR, USA.

Purpose: To evaluate whether the onset of pediatric refractory status epilepticus (rSE) is related to time of day.

Method: We analyzed the time of day for the onset of rSE in this prospective observational study performed from June 2011 to May 2019 in pediatric patients (1 month to 21 years of age). We evaluated the temporal distribution of pediatric rSE utilizing a cosinor analysis. We calculated the midline estimating statistic of rhythm (MESOR) and amplitude. MESOR is the estimated mean number of rSE episodes per hour if they were evenly distributed. Amplitude is the difference between MESOR and maximum rSE episodes/hour, or between MESOR and minimum rSE episodes/hour. We also evaluated the temporal distribution of time to treatment.

Results: We analyzed 368 patients (58% males) with a median (p - p) age of 4.2 (1.3-9.7) years. The MESOR was 15.3 (95% CI: 13.9-16.8) and the amplitude was 3.2 (95% CI: 1.1-5.3), p = 0.0024, demonstrating that the distribution is not uniform, but better described as varying throughout the day with a peak in the morning (11am-12 pm) and trough at night (11 pm-12 am). The duration from rSE onset to application of the first non-benzodiazepine antiseizure medication peaked during the early morning (2am-3 am) with a minimum during the afternoon (2 pm-3 pm) (p = 0.0179).

Conclusions: The distribution of rSE onset is not uniform during the day. rSE onset shows a 24-h distribution with a peak in the mid-morning (11am-12 pm) and a trough at night (11 pm-12am).
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http://dx.doi.org/10.1016/j.seizure.2019.06.017DOI Listing
August 2019

Novel drugs and early polypharmacotherapy in status epilepticus.

Seizure 2019 May 7;68:79-88. Epub 2018 Aug 7.

Department of Neurology, Division of Pediatric Neurology. University of Washington School of Medicine, Seattle, WA, USA.

Purpose: Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE.

Method: Literature review.

Results: New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABA receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABA synaptic receptors. Novel treatment approaches target GABA synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents.

Conclusions: Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes.
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http://dx.doi.org/10.1016/j.seizure.2018.08.004DOI Listing
May 2019

Status epilepticus prevention, ambulatory monitoring, early seizure detection and prediction in at-risk patients.

Seizure 2019 May 18;68:31-37. Epub 2018 Sep 18.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Purpose: Status epilepticus is an often apparently randomly occurring, life-threatening medical emergency which affects the quality of life in patients with epilepsy and their families. The purpose of this review is to summarize information on ambulatory seizure detection, seizure prediction, and status epilepticus prevention.

Method: Narrative review.

Results: Seizure detection devices are currently under investigation with regards to utility and feasibility in the detection of isolated seizures, mainly in adult patients with generalized tonic-clonic seizures, in long-term epilepsy monitoring units, and occasionally in the outpatient setting. Detection modalities include accelerometry, electrocardiogram, electrodermal activity, electroencephalogram, mattress sensors, surface electromyography, video detection systems, gyroscope, peripheral temperature, photoplethysmography, and respiratory sensors, among others. Initial detection results are promising, and improve even further, when several modalities are combined. Some portable devices have already been U.S. FDA approved to detect specific seizures. Improved seizure prediction may be attainable in the future given that epileptic seizure occurrence follows complex patient-specific non-random patterns. The combination of multimodal monitoring devices, big data sets, and machine learning may enhance patient-specific detection and predictive algorithms. The integration of these technological advances and novel approaches into closed-loop warning and treatment systems in the ambulatory setting may help detect seizures sooner, and tentatively prevent status epilepticus in the future.

Conclusions: Ambulatory monitoring systems are being developed to improve seizure detection and the quality of life in patients with epilepsy and their families.
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http://dx.doi.org/10.1016/j.seizure.2018.09.013DOI Listing
May 2019

Patterns of epileptic seizure occurrence.

Brain Res 2019 01 23;1703:3-12. Epub 2018 Feb 23.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: The occurrence of epileptic seizures in seemingly random patterns takes a great toll on persons with epilepsy and their families. Seizure prediction may markedly improve epilepsy management and, therefore, the quality of life of persons with epilepsy.

Methods: Literature review.

Results: Seizures tend to occur following complex non-random patterns. Circadian oscillators may contribute to the rhythmic patterns of seizure occurrence. Complex mathematical models based on chaos theory try to explain and even predict seizure occurrence. There are several patterns of epileptic seizure occurrence based on seizure location, seizure semiology, and hormonal factors, among others. These patterns are most frequently described for large populations. Inter-individual variability and complex interactions between the rhythmic generators continue to make it more difficult to predict seizures in any individual person. The increasing use of large databases and machine learning techniques may help better define patterns of seizure occurrence in individual patients. Improvements in seizure detection -such as wearable seizure detectors- and in seizure prediction -such as machine learning techniques and artificial as well as neuronal networks- promise to provide further progress in the field of epilepsy and are being applied to closed-loop systems for the treatment of epilepsy.

Conclusions: Seizures tend to occur following complex and patient-specific patterns despite their apparently random occurrence. A better understanding of these patterns and current technological advances may allow the implementation of closed-loop detection, prediction, and treatment systems in routine clinical practice.
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http://dx.doi.org/10.1016/j.brainres.2018.02.032DOI Listing
January 2019

[Is attention deficit hyperactivity disorder associated with other prevalent pathologies of early childhood?].

Rev Neurol 2015 Feb;60 Suppl 1:S109-13

Hospital Son Llatzer, 07198 Son Ferriol, Espana.

Aim: To determine whether attention deficit hyperactivity disorder (ADHD) is associated with other prevalent medical pathologies of the paediatric age.

Development: Several paediatric pathologies were selected with the aim of reviewing their association with ADHD: in paediatric pulmonology, asthma and other allergic processes; in paediatric neurology, headache and febrile seizures; in paediatric gastroenterology, diarrhoea, constipation, abdominal pain, gastroesophageal reflux and infection by Helicobacter pylori; in paediatric nephrology, enuresis; in paediatric cardiology, bruits and congenital heart disease; in paediatric endocrinology, thyroid disorders and obesity; and in paediatric ophthalmology, ametropia and strabismus.

Conclusions: Several studies were found that related ADHD with allergic processes, overweight/obesity, peripheral resistance to thyroid hormone, enuresis, febrile seizures, headache, congenital heart disease, ophthalmic disorders and tooth decay, with some controversial issues and details still to be defined. It can be concluded that further interdisciplinary studies are needed to clarify the associations and underlying mechanisms involved, so as to be able to gain a deeper understanding of the complex entity of ADHD and to suggest preventive, diagnostic and therapeutic interventions with regard to its comorbidities.
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February 2015
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