New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome.

PURPOSE OF REVIEW: The concept and understanding of new-onset refractory status epilepticus (NORSE), and its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES) have evolved in the recent past. This review aims to summarize the recent developments in the pathophysiology, diagnosis and management of these challenging conditions. RECENT FINDINGS: NORSE and FIRES can have many different causes. Although the list of possible causes is still growing, they mostly fall in the categories of autoimmune encephalitis and genetic disorders. However, despite extensive investigations, most cases of NORSE and FIRES remain cryptogenic. Recent studies have pointed towards the key role of autoinflammation as a unifying pathophysiological mechanism in these cases. These findings also support the use of immunomodulatory treatment in this setting. Consensus recommendations on the management of NORSE and FIRES have recently been published. SUMMARY: NORSE and FIRES remain challenging conditions to diagnose and treat. Recent findings from clinical and basic research and new recommendations, reviewed in this article, contribute to an emerging framework for management and future research.

Investigation of the low glutamate diet as an adjunct treatment for pediatric epilepsy: A pilot randomized controlled trial.

INTRODUCTION: Current dietary therapies for epilepsy have side effects and are low in nutrients, which would make an alternative dietary treatment, which addresses these issues, advantageous. One potential option is the low glutamate diet (LGD). Glutamate is implicated in seizure activity. Blood brain barrier permeability in epilepsy could enable dietary glutamate to reach the brain and contribute to ictogenesis. OBJECTIVE: to assess the LGD as an adjunct treatment for pediatric epilepsy. METHODS: This study was a nonblinded, parallel, randomized clinical trial. The study was conducted virtually due to COVID-19 and registered on clinicaltrials.gov (NCT04545346). Participants were eligible if they were between the ages of 2 and 21 with ≥4 seizures per month. Baseline seizures were assessed for 1-month, then participants were allocated via block randomization to the intervention month (N=18), or a wait-listed control month followed by the intervention month (N=15). Outcome measures included seizure frequency, caregiver global impression of change (CGIC), non-seizure improvements, nutrient intake, and adverse events. RESULTS: Nutrient intake significantly increased during the intervention. No significant differences in seizure frequency were observed between intervention and control groups. However, efficacy was assessed at 1-month compared to the standard 3-months in diet research. Additionally, 21% of participants were observed to be clinical responders to the diet. Overall health (CGIC) significantly improved in 31%, 63% experienced ≥1 non-seizure improvements, and 53% experienced adverse events. Clinical response likelihood decreased with increasing age (0.71 [0.50-0.99], p=0.04), as did the likelihood of overall health improvement (0.71 [0.54-0.92], p=0.01). DISCUSSION: This study provides preliminary support for the LGD as an adjunct treatment before epilepsy becomes drug resistant, which is in contrast to the role of current dietary therapies in drug resistant epilepsy.

Scoping review of rational polytherapy in patients with drug-resistant epilepsy.

There is a paucity of literature regarding the optimal selection of combination antiseizure medications (ASMs) for drug-resistant epilepsy (DRE). The aim of this scoping review is to evaluate current evidence related to "rational polytherapy" among adults with DRE. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-SCr) guidelines, PubMed, ProQuest, CINAHL, and Cochrane databases were searched using DRE- and polytherapy-related keywords. The exclusion criteria applied included: non-English; non-human studies; non-research studies; participants less than 18 years; status epilepticus; ASM monotherapy; and certain ASMs. In Covidence, two researchers independently reviewed articles for inclusion at each phase, with a third resolving conflicts. Data were extracted, with quality appraisal using the Mixed Methods Appraisal Tool (MMAT). Of the 6477 studies imported for screening, 33 studies were included. Clinical, humanistic, and economic outcomes were reported by 26, 12, and one study, respectively. Common efficacy-related clinical outcomes included ≥50% reduction in seizure frequency (n = 14), seizure freedom (n = 14), and percent reduction in seizure frequency (n = 8). Common humanistic outcomes included quality of life (n = 4), medication adherence (n = 2), sleep-related outcomes (n = 2), and physician and patient global assessments (n = 2). The economic study reported quality-adjusted life years. The median MMAT score was 80 (range: 60-100). Two studies referenced the standard definition of DRE, whereas five studies did not specifically define DRE. Gaps in the literature include limited generalizability, minimal reports in pregnancy, and lack of optimal ASM combinations, among others. Strengths of the evidence include addressing a variety of outcomes. Inconsistent definitions of DRE, small sample sizes, and heterogeneity among studies limit the ability to draw meaningful conclusions. Optimal combinations of ASMs for rational polytherapy for DRE is unclear.

Impact of the COVID-19 Pandemic on Epilepsy Center Practice in the United States.

BACKGROUND AND OBJECTIVES: Persons with epilepsy, especially those with drug resistant epilepsy (DRE), may benefit from inpatient services such as admission to the epilepsy monitoring unit (EMU) and epilepsy surgery. The COVID-19 pandemic caused reductions in these services within the US during 2020. This article highlights changes in resources, admissions, and procedures among epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC). METHODS: We compared data reported in 2019, prior to the COVID-19 pandemic, and 2020 from all 260 level 3 and level 4 NAEC accredited epilepsy centers. Data were described using frequency for categorical variables and median for continuous variables and were analyzed by center level, center population category, and geographical location. Qualitative responses from center directors to questions regarding the impact from COVID-19 were summarized utilizing thematic analysis. Responses from the NAEC center annual reports as well as a supplemental COVID-19 survey were included. RESULTS: EMU admissions declined 23% (-21,515) in 2020, with largest median reductions in level 3 centers [-55 admissions (-44%)] and adult centers [-57 admissions (-39%)]. The drop in admissions was more substantial in the East North Central, East South Central, Mid Atlantic, and New England US Census divisions. Survey respondents attributed reduced admissions to re-assigning EMU beds, restrictions on elective admissions, reduced staffing, and patient reluctance for elective admission. Treatment surgeries declined by 371 cases (5.7%), with the largest reduction occurring in VNS implantations [-486 cases (-19%)] and temporal lobectomies [-227 cases (-16%)]. All other procedure volumes increased, including a 35% (54 cases) increase in corpus callosotomies. DISCUSSION: In the US, access to care for persons with epilepsy declined during the COVID-19 pandemic in 2020. Adult patients, those relying on level 3 centers for care, and many persons in the eastern half of the US were most affected.

Telemedicine- versus outpatient-based initiation and management of ketogenic diet therapy in children with drug-resistant epilepsy during the COVID-19 pandemic.

INTRODUCTION: Initiation of ketogenic diet therapies (KDT) for pediatric epilepsy is usually done on an inpatient basis and the diet is managed during clinical appointments following a protocol of visits and routine tests. Because of the 2019 coronavirus disease (COVID-19) pandemic and the associated lock-down measures, we switched from outpatient to telemedicine-based KDT initiation. OBJECTIVE: To explore the feasibility, effectiveness, and safety of online KDT initiation and follow-up by comparing a group of children with drug-resistant epilepsy that was managed by telemedicine compared to a group that was treated on an outpatient basis. MATERIALS AND METHODS: An observational study was conducted in two groups of patients with drug-resistant epilepsy who initiated KDT and were followed up with an online versus an outpatient modality by the interdisciplinary KDT team of Hospital Pediatria JP Garrahan in Buenos Aires, Argentina. Dietary compliance, ketosis, retention rate, adverse effects, number of contacts, and clinical outcome were evaluated at 1, 3, and 6 months on the diet. RESULTS: Overall, 37 patients were included, of whom 18 started the KD by telemedicine and 19 on an outpatient basis. Minimum follow-up of the patients was 6 months. All patients received the classic ketogenic diet. No statistical differences between the two groups regarding efficacy and safety of the diet were found. CONCLUSIONS: Our results support the feasibility and safety of initiating and management of KDT by telemedicine. Patients and their families should be carefully selected in order to guarantee a good outcome.

About gladiators and a sacred disease.

In this special edition of the Biomedical Journal the reader gains an insight into drug-resistant epilepsy and according treatment approaches involving deep brain stimulation, the ketogenic diet and fecal microbiota transplant. Another emphasis is put on personalized medicine strategies, and covered in articles about the use of natriuretic peptides against cancer, along with an article about companion diagnostics involving extracellular vesicles. Recurrent infection with Clostridium difficile, associated risk factors and therapeutic options are discussed. We learn about a mechanism that helps Leishmania evade a host control mechanism, receive an update about human adenovirus and are presented with characteristic magnetic resonance neuroimaging in COVID-19 pediatric patients. An advanced assessment in pediatric septic shock and an improved model for a pediatric early warning system are proposed. Some of the genetic causes of renal hypomagnesemia are explored, the impact of air pollution on children is examined, and an antisiphon device is described for surgical treatment of hydrocephalus. The relation between energy metabolism, circadian rhythm and its influence on the ATPase in the SCN are investigated, and among others some of the genetics influencing smoking duration and lung cancer. Finally it is discussed how embryo quality can be improved in in vitro fertilization, and what impact high estradiol has on blastocyst implantation. The outcome of surgery to correct mandibular deficiency is assessed, and in two letters the inclusion of observational studies in the evaluation of clinical trials related to COVID-19 is elaborated.

[Telemedicine and epilepsy: healthcare experience of a national reference center during the COVID-19 pandemic]. / Telemedicina y epilepsia: experiencia asistencial de un centro de referencia nacional durante la pandemia de COVID-19.

INTRODUCTION: Countries worldwide are having to cope with the COVID-19 pandemic caused by SARS-CoV-2. The burden on their national health systems is currently at unprecedented levels. Telemedicine care was initiated at an early stage in our centre. PATIENTS AND METHODS: We conducted a descriptive and retrospective study to evaluate the usefulness of telemedicine during lockdown in our centre. Patients included in the study had a clinical diagnosis of epilepsy, with two visits via telemedicine, who had been followed up for at least six months during the normal situation prior to the COVID-19 pandemic and two face-to-face consultations during the same period. RESULTS: A total of 115 patients were included. The average age was 29 years, 53% were males, 52.2% had focal epilepsy, 58.3% with a structural causation and 57.4% had difficult-to-treat epilepsy. The mean number of seizures prior to lockdown was 9.73/month and 6.54/month during lockdown. The number of patients who were seizure-free when lockdown ended was higher than that observed in the phase before it began: 54 versus 45 out of 115. CONCLUSIONS: Telemedicine is a very useful strategy for monitoring the course, progress and therapeutic changes in epileptic patients in the short and medium term. The reduction in the seizure frequency can be sustained in the medium term, not only in the short term as corroborated in previous studies. Telemedicine allows access to virtually all patients and closer monitoring.

TITLE: Telemedicina y epilepsia: experiencia asistencial de un centro de referencia nacional durante la pandemia de COVID-19.Introducción. El mundo entero está afrontando la pandemia por COVID-19 causada por el SARS-CoV-2. Los sistemas de salud nacionales están sometidos a niveles de sobrecarga sin precedentes. En nuestro centro se inició de forma temprana la asistencia a través de telemedicina. Pacientes y métodos. Es un estudio descriptivo y retrospectivo para evaluar la utilidad de la telemedicina durante el confinamiento en nuestro centro. Se incluyó a los pacientes con diagnóstico clínico de epilepsia, con dos asistencias a través de telemedicina, que tuvieran seguimiento durante al menos seis meses durante la situación de normalidad previa a la pandemia por COVID-19 y dos consultas presenciales durante ese mismo período. Resultados. Se incluyó a 115 pacientes. La media de edad fue de 29 años, el 53% fueron varones, el 52,2% con epilepsia focal, el 58,3% de etiología estructural y el 57,4% presentaba epilepsia de difícil control. La media de crisis preconfinamiento fue de 9,73/mes y de 6,54/mes durante el confinamiento. El número de pacientes libres de crisis fue mayor al final del confinamiento respecto a la fase preconfinamiento, 54 frente a 45/115. Conclusiones. La telemedicina es una estrategia de mucha utilidad en la monitorización de la evolución, el control evolutivo y los cambios terapéuticos en pacientes epilépticos a corto y medio plazo. La reducción de la frecuencia de crisis puede mantenerse a medio plazo, no sólo a corto plazo como se corroboró en estudios previos. La telemedicina permite acceder a prácticamente la totalidad de los pacientes y realizar un seguimiento más cercano.

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies.

BACKGROUND AND PURPOSE: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. METHODS: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. RESULTS: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called 'cryptogenic NORSE'. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. CONCLUSIONS: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

The future is now: pediatric neuropsychological presurgical epilepsy evaluation in the age of COVID-19.

The objective of this brief report is to review an assessment paradigm for conducting virtual neuropsychological pre-surgical evaluations in the context of the COVID-19 pandemic. A multidisciplinary epilepsy team at a Level 4 epilepsy center within a large children's academic medical center convened to discuss the challenges and possible solutions for Phase II evaluations for pediatric patients with pharmacoresistant epilepsy during the COVID-19 pandemic. The neuropsychologists explored evidence-based methods of virtual evaluation and developed a systematic decision-making process for youth requiring a Phase II evaluation. We propose models of assessment which prioritize teleneuropsychology when possible to reduce the risk of infection: (1) evaluation with directly administered tests through a completely virtual format; (2) virtual/in-person hybrid evaluation; and (3) clinical observation/interview in a virtual format supplemented by survey data. These models are illustrated by three cases. Using virtual assessment models, the team was able to meet the urgent patient care needs and collect useful data while minimizing the risk of virus spread. The paradigms presented may be useful examples for other multidisciplinary surgical teams interested in incorporating teleneuropsychology into their practices.

New-onset refractory status epilepticus following the ChAdOx1 nCoV-19 vaccine.

Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Developing an effective and reliable vaccine was emergently pursued to control the dramatic spread of the global pandemic. The standard stages for vaccine development were unprecedentedly accelerated over a few months. We report a case of new-onset refractory status epilepticus (NORSE) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute the occurrence of NORSE to the vaccine due to the temporal relationship and the lack of risk factors for epilepsy in the patient. This report adds to the literature a possible rare side effect of a COVID-19 vaccine and contributes to the extremely limited literature on potential neurological side effects of viral vector vaccines. Healthcare providers should be aware of the possibility of post-vaccination epilepsy. The patient had recurrent seizures that were refractory to conventional antiepileptic drug therapy with a dramatic response to immunotherapy with pulse steroids and plasmapheresis. This likely reflects an underlying autoimmune mechanism in the genesis of post-vaccination generalized seizures without fever. Further research is needed to probe and study the exact mechanism at a more molecular level.

Evaluation of E-Health Applications for Paediatric Patients with Refractory Epilepsy and Maintained on Ketogenic Diet.

E-health technologies improve healthcare quality and disease management. The aim of this study was to develop a ketogenic diet management app as well as a website about this dietary treatment and to evaluate the benefits of giving caregivers access to various web materials designed for paediatric patients with refractory epilepsy. Forty families participated in the questionnaire survey, from January 2016 to March 2016. All caregivers were exposed to paper-based materials about the ketogenic diet, whereas only 22 received the app, called KetApp, and videos produced by dieticians. Caregivers with free access to web materials were more satisfied than the others with the informative material provided by the centre (p ≤ 0.001, Mann-Whitney test). Indeed, they showed a better attitude towards treatment, and they became more aware of dietary management in comparison to the control group (p ≤ 0.001). Moreover, caregivers provided with web materials were stimulated to pursue the treatment (p = 0.002) and to introduce it to their children and other people (p = 0.001). Additionally, caregivers supplied with web materials were more willing to help other families in choosing the ketogenic diet (p = 0.004). Overall, these findings indicate that web materials are beneficial for caregivers of paediatric patients with refractory epilepsy in our centres. Thus, the use of e-health applications could be a promising tool in the daily aspects of ketogenic diet management, and it is especially of value in the attempt to start or maintain the diet during the ongoing COVID-19 pandemic crisis.

Challenges in telemedicine for adult patients with drug-resistant epilepsy undergoing ketogenic diet treatment during the COVID-19 pandemic in the public healthcare system in Brazil.

Hygienic and sanitary measures and social distancing policies implemented during the new coronavirus disease - COVID-19 - pandemic have altered the care and follow-up provided by healthcare professionals for patients with chronic diseases, including patients with epilepsy (PWEs). Telemedicine has become a solution for the healthcare of PWEs in many developed countries. In this short communication, we trace a particular perspective for the application of telemedicine for PWEs undergoing ketogenic diet (KD) treatment, considering the social and economic difficulties faced by healthcare teams in resource-poor countries, such as Brazil. During the pandemic, financial strain was the main impediment to following KD. The pandemic increased socioeconomic insecurity and access to KD-related products, as well as increasing anxiety in 71% of PWE, impacting their KD treatment follow-up. The challenges of telemedicine in Brazil include not only social and economic issues but also access to food, healthcare services, and education for the population, in addition to digital inclusion.

Telemedicine, drug-resistant epilepsy, and ketogenic dietary therapies: A patient survey of a pediatric remote-care program during the COVID-19 pandemic.

OBJECTIVE: The purpose of this study was to assess parent satisfaction with the management of ketogenic diet therapies (KDTs) through telemedicine using WhatsApp as the main tool. METHODS: Parent satisfaction was longitudinally evaluated through questionnaires. The survey was developed with Google Questionnaire forms and sent via WhatsApp. The questionnaire consisted of 13 items concerning the management of KDTs using telemedicine in the context of the coronavirus disease 2019 (COVID-19) pandemic. Our population of patients has limited financial resources and low levels of education. Given that many families did not have either computers or WIFI, or any other access to information or communication technology, WhatsApp was chosen as a tool as it was available on the cell phones of all families and the professionals. RESULTS: Our survey showed that 96.3% of the parents were satisfied with the management of KDTs through telemedicine. The main benefits observed were the possibility of continuing treatment during the COVID-19 pandemic and the ease of accessing the professional team from the comfort of their home. Overall, 72.2% of the families would recommend using telemedicine for KDTs in any situation regardless of the pandemic. None of the families reported that they would recommend against treatment by telemedicine. The availability of a social support network (parents WhatsApp group) coordinated by professionals from the KDT team was considered to be useful by most respondents (90%). CONCLUSIONS: Our study suggests that management of children with DRE on KDTs through telemedicine is feasible, well accepted by the families, and probably as safe as conventional medicine. WhatsApp may be an interesting telemedicine tool to start and maintain KDTs.

Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.

There have been multiple descriptions of seizures during the acute infectious period in patients with COVID-19. However, there have been no reports of status epilepticus after recovery from COVID-19 infection. Herein, we discuss a patient with refractory status epilepticus 6 weeks after initial infection with COVID-19. Extensive workup demonstrated elevated inflammatory markers, recurrence of a positive nasopharyngeal SARS-CoV-2 polymerase chain reaction, and hippocampal atrophy. Postinfectious inflammation may have triggered refractory status epilepticus in a manner similar to the multisystemic inflammatory syndrome observed in children after COVID-19.

Severe psychological distress among patients with epilepsy during the COVID-19 outbreak in southwest China.

OBJECTIVE: To compare the severity of psychological distress between patients with epilepsy and healthy controls during the COVID-19 outbreak in southwest China, as well as identify potential risk factors of severe psychological distress among patients with epilepsy. METHODS: This cross-sectional case-control study examined a consecutive sample of patients older than 15 years treated at the epilepsy center of West China Hospital between February 1 and February 29, 2020. As controls, sex- and age-matched healthy visitors of inpatients (unrelated to the patients) were also enrolled during the same period. Data on demographics and attention paid to COVID-19 were collected by online questionnaire, data on epilepsy features were collected from electronic medical records, and psychological distress was evaluated using the 6-item Kessler Psychological Distress Scale (K-6). Potential risk factors of severe psychological distress were identified using multivariate logistic regression. RESULTS: The 252 patients and 252 controls in this study were similar along all demographic variables except family income. Patients with epilepsy showed significantly higher K-6 scores than healthy controls and spent significantly more time following the COVID-19 outbreak (both P < .001). Univariate analyses associated both diagnosis of drug-resistant epilepsy and time spent paying attention to COVID-19 with severe psychological distress (defined as K-6 score >12; both P ≤ .001). Multivariate logistic regression identified two independent predictors of severe psychological distress: time spent paying attention to COVID-19 (odds ratio [OR] = 1.172, 95% confidence interval [CI] = 1.073-1.280) and diagnosis of drug-resistant epilepsy (OR = 0.283, 95% CI = 0.128-0.623). SIGNIFICANCE: During public health outbreaks, clinicians and caregivers should focus not only on seizure control but also on mental health of patients with epilepsy, especially those with drug-resistant epilepsy. K-6 scores > 12 indicate severe psychological distress. This may mean, for example, encouraging patients to engage in other activities instead of excessively following media coverage of the outbreak.