RESUMEN
OBJECTIVE: To describe the organization of the Epilepsy Learning Healthcare System (ELHS), a network that aims to improve care outcomes for people with epilepsy (PWE). MATERIALS AND METHODS: Patients and family partners, providers, researchers, epidemiologists, and other leaders collaborated to recruit epilepsy centers and community services organizations into a novel learning network. A multidisciplinary Coordinating Committee developed ELHS governance and organizational structure, including four key planning Cores (Community, Clinical, Quality Improvement, and Data). Through Quality Improvement (QI) methodology grounded in the Institute for Healthcare Improvement (IHI) model, including iterative Plan-Do-Study-Act (PDSA) rapid learning cycles and other learning and sharing sessions, ELHS equipped epilepsy centers and community organizations with tools to standardize, measure, share, and improve key aspects of epilepsy care. The initial learning cycles addressed provider documentation of seizure frequency and type, and also screening for medication adherence barriers. Rapid learning cycles have been carried out on these initial measures in both clinical centers and community-based settings. Additional key measures have been defined for quality of life, screening, and treatment for mental health and behavioral comorbidities, transition from pediatric to adult care, counseling for women and girls living with epilepsy, referral for specialty care, and prevention and treatment of seizure clusters and status epilepticus. RESULTS: It is feasible to adopt a learning healthcare system framework in epilepsy centers and community services organizations. Through structured collaboration between epilepsy care providers, community support organizations, PWE, and their families/caregivers we have identified new opportunities to improve outcomes that are not available in traditional care models.
Asunto(s)
Epilepsia , Aprendizaje del Sistema de Salud , Transición a la Atención de Adultos , Adulto , Niño , Epilepsia/terapia , Femenino , Humanos , Evaluación de Resultado en la Atención de Salud , Calidad de VidaRESUMEN
BACKGROUND: Epilepsy is the 4th most common neurological disorder and is characterized by recurrent, unpredictable seizures. The ability to forecast seizures is a significant unmet need and would have a transformative effect on the lives of people living with epilepsy. In an effort to address this need, the Epilepsy Foundation has committed effort and resources to promote the development of seizure forecasting devices (SFD). OBJECTIVE: To promote user-centered design of future SFD, we sought to quantify patient and caregiver preferences for the potential benefits and risks of SFD. METHODS: A community-centered approach was used to develop a survey incorporating a novel best-worst scaling (BWS) to assess preferences for SFD. A main-effect orthogonal array was used to design and generate 18 "prototypes" that systematically varied across six attributes: seizure forecasting probability, seizure forecasting range, inaccuracy of forecasting, amount of time required to use the device, how the device is worn, and cost. The dependent variable was the attributes that respondents selected the best and worst in each profile, and a choice model was estimated using conditional logistic regression, which was also stratified and compared across patients and caregivers. Respondents also indicated that they would accept each of the prototype SFDs if it were real. These acceptance data and net monetary benefits (relative to the least preferred SFD) were explored. RESULTS: There were 633 eligible respondents; 493 (78%) completed at least one task. Responses indicated that 346 (68%) had epilepsy, and 147 (29%) were primary caregivers or family members of someone with epilepsy. The data show that short forecasting range is the most favored among experimental attributes, followed by mid forecasting range and notification of high chance of seizure. Having the device implanted is the least favorable attribute. Stated preferences differed between patients and caregivers (pâ¯<â¯0.001) for range of forecasting and inaccuracy of device. Caregivers preferred any range of forecasting, regardless of length, more than patients. Patients cared less about inaccuracy of the device compared to caregivers. The groups also differ in impact of fear of having seizures (versus actually having seizures) (pâ¯=â¯0.034) and on device acceptance. The acceptance of devices ranged from 42.3% to 95%, with caregivers being more likely to use a device (pâ¯<â¯0.05) for the majority of device profiles. Acceptance of devices varied with net monetary benefit of the best device being $717.44 more per month relative to the least preferred device. CONCLUSION: Our finding extends previous calls for seizure forecasting devices by demonstrating the value that they might provide to patients and caregivers affected by epilepsy and the feature that might be most and least desirable. In addition to guiding device development, the data can help inform regulatory decisions makers.
Asunto(s)
Toma de Decisiones , Epilepsia , Familia , Prioridad del Paciente , Convulsiones , Adulto , Cuidadores , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Encuestas y CuestionariosRESUMEN
On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.
Asunto(s)
Encefalopatías/genética , Epilepsia/etiología , Epilepsia/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Simbiosis/genética , Animales , Anticonvulsivantes/uso terapéutico , Encefalopatías/complicaciones , Encefalopatías/tratamiento farmacológico , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética , Epilepsia/tratamiento farmacológico , Humanos , Modelos Moleculares , Canal de Sodio Activado por Voltaje NAV1.1/genética , Canal de Sodio Activado por Voltaje NAV1.6/metabolismo , FenotipoRESUMEN
Background and Objectives: Accurate and reliable seizure data are essential for evaluating treatment strategies and tracking the quality of care in epilepsy clinics. This quality improvement project aimed to increase seizure documentation (i.e., documentation of seizure frequency from 80% to 100%, date of last seizure from 35% to 50%, and International League Against Epilepsy (ILAE) seizure classification from 35% to at least 50%) over 6 months. Methods: We surveyed 7 epileptologists to determine their perceived seizure frequency, ILAE classification, and date of last seizure documentation habits. Baseline data were collected weekly from September to December 2021. Subsequently, we implemented a newly created flowsheet in our Electronic Health Record (EHR) based on the Epilepsy Learning Healthcare System (ELHS) Case Report Forms to increase seizure documentation in a standardized way. Two epileptologists tested this flowsheet tool in their epilepsy clinics between February 2022 and July 2022. Data were collected weekly and compared with documentation from other epileptologists within the same group. Results: Epileptologists at our center believed they documented seizure frequency for 84%-87% of clinic visits, which aligned with baseline data collection, showing they recorded seizure frequency for 83% of clinic visits. Epileptologists believed they documented ILAE classification for 47%-52% of clinic visits, and baseline data showed this was documented in 33% of clinic visits. They also reported documenting the date of the last seizure for 52%-63% of clinic visits, but this occurred in only 35% of clinic visits. After implementing the new flowsheet, documentation increased to nearly 100% for all fields being completed by the providers who tested the flowsheet. Discussion: We demonstrated that by implementing an easy-to-use standardized EHR documentation tool, our documentation of critical metrics, as defined by the ELHS, improved dramatically. This shows that simple and practical interventions can substantially improve clinically meaningful documentation.
RESUMEN
PURPOSE: An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials. METHODS: This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries. KEY FINDINGS: Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by epilepsy.com and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries. Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data. Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a "real-world" environment. Diary-based studies can also be useful as descriptive "snapshots" of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication. Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious. SIGNIFICANCE: Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials.
Asunto(s)
Investigación Biomédica , Proyectos de Investigación , Convulsiones , Humanos , Cooperación del Paciente , Reproducibilidad de los ResultadosRESUMEN
The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.
Asunto(s)
Recolección de Datos/normas , Epilepsia/epidemiología , National Institute of Neurological Disorders and Stroke (U.S.)/normas , Desarrollo de Programa/normas , Anticonvulsivantes/uso terapéutico , Recolección de Datos/tendencias , Epilepsia/diagnóstico , Epilepsia/terapia , Humanos , National Institute of Neurological Disorders and Stroke (U.S.)/tendencias , Proyectos de Investigación/normas , Estados UnidosRESUMEN
OBJECTIVE: To incorporate standardized documentation into an epilepsy clinic and to use these standardized data to compare patients' perception of epilepsy diagnosis to provider documentation. METHODS: Using quality improvement methodology, we implemented interventions to increase documentation of epilepsy diagnosis, seizure frequency, and type from 49.8% to 70% of adult nonemployee patients seen by 6 providers over 5 months of routine clinical care. The main intervention consisted of an interactive SmartPhrase that mirrored a documentation template developed by the Epilepsy Learning Healthcare System. We assessed the weekly proportion of complete SmartPhrases among eligible patient encounters with a statistical process control chart. We used a subset of patients with established epilepsy care linked to existing patient-reported survey data to examine the proportion of patient-to-provider agreement on epilepsy diagnosis (yes vs no/unsure). We also examined sociodemographic and clinical characteristics of patients who disagreed vs agreed with provider's documentation of epilepsy diagnosis. RESULTS: The median SmartPhrase weekly completion rate was 78%. Established patients disagreed with providers with respect to epilepsy diagnosis in 18.5% of encounters (κ = 0.13), indicating that they did not have or were unsure if they had epilepsy despite having a provider-documented epilepsy diagnosis. Patients who disagreed with providers were similar to those who agreed with respect to age, sex, ethnicity, marital status, seizure frequency, type, and other quality-of-life measures. CONCLUSION: This project supports the feasibility of implementing standardized documentation of data relevant to epilepsy care in a tertiary epilepsy clinic and highlights an opportunity for improvement in patient-provider communication.
Asunto(s)
Documentación/normas , Epilepsia/terapia , Personal de Salud/normas , Adulto , Comunicación , Epilepsia/psicología , Femenino , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Mejoramiento de la Calidad , Calidad de Vida , Convulsiones/clasificación , Convulsiones/epidemiología , Factores Socioeconómicos , Encuestas y Cuestionarios , Centros de Atención Terciaria/normas , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the accuracy of ICD-10-CM claims-based definitions for epilepsy and classifying seizure types in the outpatient setting. METHODS: We reviewed electronic health records (EHR) for a cohort of adults aged 18+ years seen by six neurologists who had an outpatient visit at a level 4 epilepsy center between 01/2019-09/2019. The neurologists used a standardized documentation template to capture the diagnosis of epilepsy (yes/no/unsure), seizure type (focal/generalized/unknown), and seizure frequency in the EHR. Using linked ICD-10-CM codes assigned by the provider, we assessed the accuracy of claims-based definitions for epilepsy, focal seizure type, and generalized seizure type against the reference-standard EHR documentation by estimating sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). RESULTS: There were 673 eligible outpatient encounters. After review of EHRs for standardized documentation, an analytic sample consisted of 520 encounters representing 402 unique patients. In the EHR documentation, 93.5 % (n = 486/520) of encounters were with patients with a diagnosis of epilepsy. Of those, 66.0 % (n = 321/486) had ≥1 focal seizure, 41.6 % (n = 202/486) had ≥1 generalized seizure, and 7% (n = 34/486) had ≥1 unknown seizure. An ICD-10-CM definition for epilepsy (i.e., ICD-10 G40.X) achieved Sn = 84.4 % (95 % CI 80.8-87.5%), Sp = 79.4 % (95 % CI 62.1-91.3%), PPV = 98.3 % (95 % CI 96.6-99.3%), and NPV = 26.2 % (95 % CI 18.0-35.8%). The classification of focal vs generalized/unknown seizures achieved Sn = 69.8 % (95 % CI 64.4-74.8%), Sp = 79.4 % (95 % CI 72.4-85.3%), PPV = 86.8 % (95 % CI 82.1-90.7%), and NPV = 57.5 % (95 % CI 50.8-64.0%). CONCLUSIONS: Claims-based definitions using groups of ICD-10-CM codes assigned by neurologists in routine outpatient clinic visits at a level 4 epilepsy center performed well in discriminating between patients with and without a diagnosis of epilepsy and between seizure types.
Asunto(s)
Bases de Datos Factuales/normas , Registros Electrónicos de Salud/normas , Epilepsia/clasificación , Clasificación Internacional de Enfermedades/normas , Convulsiones/clasificación , Adolescente , Adulto , Estudios de Cohortes , Epilepsia/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Convulsiones/diagnóstico , Adulto JovenRESUMEN
The Epilepsy Innovation Institute (Ei2) is a new research program of the Epilepsy Foundation designed to be an innovation incubator for epilepsy. Ei2 research areas are selected based on community surveys that ask people impacted by epilepsy what they would like researchers to focus on. In their 2016 survey, unpredictability was selected as a top issue regardless of seizure frequency or severity. In response to this need, Ei2 launched the My Seizure Gauge challenge, with the end goal of creating a personalized seizure advisory system device. Prior to moving forward, Ei2 convened a diverse group of stakeholders from people impacted by epilepsy and clinicians, to device developers and data scientists, to basic science researchers and regulators, for a state of the science assessment on seizure forecasting. From the discussions, it was clear that we are at an exciting crossroads. With the advances in bioengineering, we can utilize digital markers, wearables, and biosensors as parameters for a seizure-forecasting algorithm. There are also over a thousand individuals who have been implanted with ambulatory intracranial EEG recording devices. Pairing up peripheral measurements to brain states could identify new relationships and insights. Another key component is the heterogeneity of the relationships indicating that pooling findings across groups is suboptimal, and that data collection will need to be done on longer time scales to allow for individualization of potential seizure-forecasting algorithms.
Asunto(s)
Algoritmos , Encéfalo/fisiopatología , Epilepsia/diagnóstico , Predicción/métodos , Monitorización Neurofisiológica/métodos , Convulsiones/diagnóstico , Diagnóstico por Computador/métodos , Epilepsia/fisiopatología , Humanos , Medicina de Precisión/métodos , Convulsiones/fisiopatologíaRESUMEN
The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically â¼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/psicología , Epilepsia/terapia , Efecto Placebo , Proyectos de Investigación , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación/normasRESUMEN
Tottering (tg) mice inherit a missense mutation in the Alpha1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in tottering mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in tottering mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in tottering mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in tottering mouse Purkinje cells is regulated by Purkinje cell excitability.
Asunto(s)
Células de Purkinje/enzimología , Tirosina 3-Monooxigenasa/biosíntesis , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Cerebelo/citología , Cerebelo/efectos de los fármacos , Cerebelo/enzimología , Discinesias/tratamiento farmacológico , Discinesias/fisiopatología , Femenino , Hibridación in Situ , Isradipino/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Nimodipina/farmacología , Unión Proteica , Células de Purkinje/efectos de los fármacos , ARN Mensajero/biosíntesisRESUMEN
Mutations in ion channels, or channelopathies, often lead to neurological disorders in which normal behavior is interrupted by attacks of debilitating symptoms such as pain, weakness or abnormal motor control. Attacks are often precipitated by similar stimuli, including stress, caffeine, ethanol, exercise or fatigue. The tottering mouse inherits a mutation in P/Q-type calcium channels and reliably exhibits attacks of abnormal movements, or dyskinesia. To determine if this mouse mutant is an appropriate model to study episodic neurological disorders, tottering mice were exposed to different environmental conditions or drugs known to precipitate attacks in humans. Stress, caffeine and ethanol all reliably induced attacks in tottering mice. Since calcium influx has previously been implicated in stress-induced tottering mouse attacks, the L-type calcium channel antagonist, nimodipine, and the NMDA receptor antagonist, MK 801, were tested for their ability to prevent attacks caused by caffeine or ethanol administration. Nimodipine blocked both caffeine- and ethanol-induced attacks, while MK 801 was effective against stress- and caffeine-induced attacks. These results support a common role for excess neuronal excitability and increased calcium influx in attacks triggered by diverse agents. Together, these results suggest that the tottering mouse is a novel model to investigate triggers of episodic neurological disorders.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/genética , Corea/fisiopatología , Animales , Anticonvulsivantes/farmacología , Cafeína/farmacología , Señalización del Calcio/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Corea/genética , Corea/psicología , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Ambiente , Antagonistas de Aminoácidos Excitadores/farmacología , Iluminación , Ratones , Ratones Mutantes Neurológicos , Nimodipina/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Restricción Física , Convulsiones/fisiopatología , Estrés Psicológico/psicologíaRESUMEN
On April 30th, 2011 the National Institute of Neurological Disorders and Stroke (NINDS) held a workshop to identify key problems in recent epilepsy clinical trials and propose approaches to address the barriers that impede development of new therapeutic options for epilepsy. Preliminary recommendations were made for selection criteria for subjects entered into epilepsy trials that maximize the scientific impact of the trial and increase the ability to recruit appropriate subjects efficiently and safely. These recommendations were further refined by the authors following the workshop, and subsequently shared with all NINDS workshop participants and with the participants of the 2011 AED XI workshop on epilepsy trials (approximately 200 participants) for further comment. The working group agreed to a final set of criteria that include updated considerations of subject age, clinical semiology, EEG and imaging results, use of prior and current therapies, co-occurring conditions, and suicidality, among others.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Epilepsia/tratamiento farmacológico , Selección de Paciente , Anticonvulsivantes/efectos adversos , Resistencia a Medicamentos , Electroencefalografía , Epilepsia/fisiopatología , Humanos , National Institute of Neurological Disorders and Stroke (U.S.) , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatología , Estados UnidosRESUMEN
Episodic neurological dysfunction often results from ion channel gene mutations. Despite knowledge of the mutations, the factors that precipitate attacks in channelopathies are not clear. In humans, mutations of the calcium channel gene CACNA1A are associated with attacks of neurological dysfunction in familial hemiplegic migraine and episodic ataxia type-2. In tottering mice, a mutation in the same gene causes attacks resembling paroxysmal dyskinesia. Stress, a trigger associated with human episodic disorders, reliably elicits attacks in tottering mice. Because noradrenergic neurotransmission is critical to the stress response and because noradrenergic hyperinnervation is observed in tottering mice, the role of norepinephrine in stress-induced attacks was investigated. Drugs that act at alpha-adrenergic receptors to block noradrenergic transmission prevented attacks. However, agents that facilitate noradrenergic neurotransmission failed to induce attacks. These results suggest that, while noradrenergic neurotransmission may be necessary for attacks, an increase in norepinephrine is not sufficient to induce attacks.