High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) ...and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.
Aim
To describe the experiences and unmet medical care needs of a group of parents of children with developmental and epileptic encephalopathies (DEEs) caused by the SCN1A, KCNQ2, CDKL5, PCDH19, and ...GNAO1 variants.
Method
A qualitative descriptive study was conducted. Participants were recruited using purposeful sampling. The inclusion criteria consisted of parents of children with DEEs caused by the SCN1A, KCNQ2, CDKL5, PCDH19, or GNAO1 variants, aged between 4 and 10 years old. In total, 21 parents were included. Data were acquired via researcher field notes and in‐depth interviews. A thematic analysis was performed.
Results
Three main themes were identified: (1) managing symptoms: epileptic seizures are experienced with great uncertainty and are accompanied by cognitive, behavioural, and motor symptoms; (2) accepting treatment: the ideal medication regimen is a challenge and the decision to withdraw or start a new therapy falls on the parents; and (3) therapeutic relationship and medical care: behaviours related to the health professional can hinder the therapeutic relationship with the parents. Parents are apprehensive about going to the emergency department.
Interpretation
Professionals in emergency departments should acquire better knowledge of DEEs, welcome parents, and improve treatment for the children. The results of this study can serve as a starting point for a roadmap of relevant caregiver‐reported outcomes in DEEs, to be implemented with new clinical trials and aetiology‐targeted therapies.
What this paper adds
Epileptic seizures are the symptom that is most experienced and feared by parents.
The medication regime has no defined protocol and the decision to withdraw a medication is frequently left to parents.
What this paper adds
Epileptic seizures are the symptom that is most experienced and feared by parents.
The medication regime has no defined protocol and the decision to withdraw a medication is frequently left to parents.
Parents of children with genetic developmental and epileptic encephalopathies (DEEs) face multiple challenges regarding their child's epilepsy and numerous comorbidities. However, they require the close support of healthcare professionals. One of the main problems they face is the lack of knowledge concerning DEEs among professionals when they go to the emergency department. Although they share common elements, the different genetic DEEs present special healthcare concerns which should be considered when planning resources, care, future studies of natural history, and new therapies.
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This original article is commented on by Chen on page 143 of this issue.
Spanish translation of this Original Article is available in the online issue.
Resumen
Objetivo
Describir las experiencias y las necesidades de atención médica de un grupo de progenitores de niños con encefalopatías epilépticas y del desarrollo (EED) causadas por las variantes ...SCN1A, KCNQ2, CDKL5, PCDH19 y GNAO1.
Método
Se realizó un estudio cualitativo descriptivo. Los participantes fueron reclutados mediante un muestreo intencional. Los criterios de inclusión consistieron en progenitores de niños con EED causadas por las variantes SCN1A, KCNQ2, CDKL5, PCDH19 o GNAO1, con edades comprendidas entre los 4 y los 10 años. En total, se incluyeron 21 progenitores. Los datos se obtuvieron mediante entrevistas en profundidad y notas de campo del investigador. Se realizó un análisis temático.
Resultados
Se identificaron tres temas principales: (1) Manejando los síntomas, las crisis epilépticas se viven con gran incertidumbre, y se acompañan de síntomas cognitivos, conductuales y motores que limitan la vida del niño; b) Aceptando el tratamiento, la pauta de la medicación idónea es un reto, la decisión de retirar o comenzar una nueva terapia recae en los progenitores; y c) Relación terapéutica y atención médica, existen comportamientos y acciones del profesional que facilitan o dificultan la relación terapéutica con los progenitores. Acudir al servicio de urgencias es vivido con recelo por los progenitores.
Interpretación
Los profesionales de los servicios de urgencias deben conocer mejor las EED, acoger a los progenitores y mejorar el tratamiento de los niños. Los resultados de este estudio pueden servir como punto de partida para una hoja de ruta de los resultados relevantes reportados por los cuidadores de las EED, a implementar nuevos ensayos clínicos y terapias dirigidas a la etiología.
Qué añade este documento
Las crisis epilépticas son el síntomas más experimentado y temido por los progenitores en las EED.
La pauta de la medicación no tiene un protocolo definido y la decisión de retirar una medicación recae en las manos de los progenitores.
Qué añade este documento
Las crisis epilépticas son el síntomas más experimentado y temido por los progenitores en las EED.
La pauta de la medicación no tiene un protocolo definido y la decisión de retirar una medicación recae en las manos de los progenitores.
This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering ...relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.
Abstract Objective Epilepsy requires continuous medical attention from multiple healthcare specialists, specialized facilities, and community‐based care. In Spain, there is no standardized approach ...to epilepsy care. The aim of this study was to identify the factors impacting on the delivery of high‐quality care by exploring key steps and barriers along the patient journey through the Spanish National Healthcare System (NHS). Methods A qualitative study was conducted using opinions and experiences of neurologists, nurses, patients, and caregivers shared in discussion meetings. Using thematic content analyses, relevant aim‐focused statements were coded according to prespecified issues in a discussion map (i.e., key steps and barriers), and sub‐coded according to emerging issues. Thematic saturation and co‐occurrence of key steps/barriers were evaluated to identify the most relevant factors impacting on the delivery of high‐quality care. Results Sixty‐five stakeholders took part in discussion meetings (36 neurologists, 10 nurses, 10 patients, and nine caregivers). Six key steps on the patient journey were identified: emergency care, diagnosis, drug therapy, follow‐up, referral, and interventional treatment. Of these, follow‐up was the most relevant step impacting on the delivery of high‐quality patient care, followed by drug therapy and diagnosis. Emergency care was considered a hot‐spot step with impact throughout the patient journey. Communication (among HCPs and between HCPs and patients) was a barrier to the delivery of high‐quality care at several stages of the patient journey, including drug therapy, follow‐up, referral, and interventional treatment. Resource availability was a barrier for diagnosis (especially for confirmation), drug therapy (drug availability), and referral (lack of professionals and specialized centers, and long waiting lists). Significance This is the first study capturing perspectives of four key stakeholders involved in epilepsy care in Spain. We provide an overview of the patient journey through the Spanish NHS and highlight opportunities to improve the delivery of patient‐centered care with a chronicity perspective. Plain Language Summary Patients with epilepsy may require prolonged medical care. In Spain, care is provided by a range of specialist and non‐specialist centers. In this study, a team of Spanish neurologists, nurses, patients and caregivers identified barriers that affect the delivery of high‐quality care for patients with epilepsy at each stage of their journey through the Spanish NHS. Specific epilepsy training for healthcare providers, appropriate resources for diagnosing and treating patients, and good communication between healthcare workers and patients were identified as important factors in providing high‐quality care for patients with epilepsy.
Pattern separation (PS) is a fundamental aspect of memory creation that defines the ability to transform similar memory representations into distinct ones, so they do not overlap when storing and ...retrieving them. Experimental evidence in animal models and the study of other human pathologies have demonstrated the role of the hippocampus in PS, in particular of the dentate gyrus (DG) and CA3. Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HE) commonly report mnemonic deficits that have been associated with failures in PS. However, the link between these impairments and the integrity of the hippocampal subfields in these patients has not yet been determined. The aim of this work is to explore the association between the ability to perform mnemonic functions and the integrity of hippocampal CA1, CA3, and DG in patients with unilateral MTLE-HE.
To reach this goal we evaluated the memory of patients with an improved object mnemonic similarity test. We then analyzed the hippocampal complex structural and microstructural integrity using diffusion weighted imaging.
Our results indicate that patients with unilateral MTLE-HE present alterations in both volume and microstructural properties at the level of the hippocampal subfields DG, CA1, CA3, and the subiculum, that sometimes depend on the lateralization of their epileptic focus. However, none of the specific changes was found to be directly related to the performance of the patients in a pattern separation task, which might indicate a contribution of various alterations to the mnemonic deficits or the key contribution of other structures to the function.
we established for the first time the alterations in both the volume and the microstructure at the level of the hippocampal subfields in a group of unilateral MTLE patients. We observed that these changes are greater in the DG and CA1 at the macrostructural level, and in CA3 and CA1 in the microstructural level. None of these changes had a direct relation to the performance of the patients in a pattern separation task, which suggests a contribution of various alterations to the loss of function.
Background
Epicrania fugax (EF) is characterized by painful paroxysms starting in a particular area of the head, and rapidly radiating forwards or backwards through the territories of different ...nerves. In former clinical descriptions, the pain moved between the posterior scalp (C2) and the frontal or periorbital area (V1), either in forward or backward direction.
Methods
We report 5 patients with a paroxysmal EF‐type pain starting in the lower face (V2 or V3) and radiating upwards.
Results
In each patient, the pain stemmed from the cheek (n = 1), the upper lip (n = 2) or the chin and mandibular area (n = 2), and then moved up to the forehead or the scalp with linear trajectory. Pain intensity was moderate (n = 1) or severe (n = 4), and pain quality was stabbing (n = 2) or electric (n = 3). The duration of attacks was very brief, lasting 1 to a few seconds. Three patients had ocular or nasal autonomic accompaniments, and 3 had triggers.
Conclusions
There seems to be a facial variant of EF. These observations could not only expand the clinical spectrum of EF but also enlarge the differential diagnosis of facial pain.
Objective
The appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed ...to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs).
Methods
This study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67–79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript.
Results
The panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS.
Conclusions
This consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.
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