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This study was designed to evaluate cardiac and respiratory dysfunction in a mouse model of sudden unexpected death in epilepsy i.e., SUDEP. We simultaneously monitored respiration via plethysmography and the electrocardiogram via telemetry before, during, and after an audiogenic seizure. DBA/1 mice responded to an acoustic stimulus with one or two cycles of circling and jumping before entering a clonic/tonic seizure. This was followed by death unless the mice were resuscitated by mechanical ventilation using room air. During the initial clonic phase, respiration declined and cardiac rhythm is slowed. By the tonic phase, respiration had ceased, atrial P-waves were absent or dissociated from the QRS complex, and heart rate had decreased from 771±11 to 252±16 bpm. Heart rate further deteriorated terminating in asystole unless the mice were resuscitated at the end of the tonic phase which resulted in abrupt recovery of P-waves and a return to normal sinus rhythm, associated with gasping. Interestingly, P-waves were preserved in the mice treated with methylatropine during the pre-ictal period (to block parasympathetic stimulation) and heart rate remained unchanged through the end of the tonic phase (765±8 vs. 748±21 bpm), but as in control, methylatropine treated mice died from respiratory arrest. These results demonstrate that a clonic/tonic seizure in the DBA/1 mouse results in abrupt and simultaneous respiratory and cardiac depression. Although death clearly results from respiratory arrest, our results suggest that seizure activates two central nervous system pathways in this model-one inhibits respiratory drive, whereas the other inhibits cardiac function via vagal efferents. The abrupt and simultaneous recovery of both respiration and cardiac function with mechanical ventilation within an early post-ictal timeframe shows that the vagal discharge can be rapidly terminated. Understanding the central mechanism associated with the abrupt cardiorespiratory dysfunction and equally abrupt recovery may provide clues for therapeutic targets for SUDEP.

We present a case of serious antidepressant discontinuation syndrome (ADDS) in a 72- year-old woman in the intensive care unit (ICU). Although this syndrome may be mild under ambulatory conditions, ICU patients can experience serious neurocognitive symptoms that are difficult to differentiate from delirium. We report delayed recognition of the ADDS in a patient in the ICU who was initially diagnosed with severe hyperactive delirium. Subsequent to hiatal hernia surgery, the patient was admitted to the ICU for aspiration and was intubated. Due to increasing agitation the patient received high doses of dexmedetomidine, fentanyl, midazolam, and propofol. The patient was treated with high doses of a serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant, duloxetine, for 2 years. However, the antidepressant was not effectively administered postsurgically due to gastroparesis. The signs and symptoms of ADDS can occur cryptogenically if they are partially masked by sedating agents. Due to concern for the discontinuation syndrome and the inability to administer duloxetine via a nasogastric tube, another SNRI, venlafaxine, was administered. Venlafaxine administration allowed unexpectedly prompt dose reduction and then total discontinuation of all sedating agents, allowing liberation from mechanical ventilation and ICU discharge. This case illustrates the importance of avoiding antidepressant discontinuation in the ICU.

We have described how the pharmacology of agents that act on the central nervous system (CNS) and endocrine system were incorporated into a case-based, multidisciplinary, integrated sophomore medical curriculum at Southern Illinois University School of Medicine (SIUSM). Faculty members from the Departments of Pharmacology, Pathology, Internal Medicine, Psychiatry, and Neurology were major participants in the CNS block, and faculty with primary expertise in radiology, epidemiology, and immunology also participated. Integrated sessions involving the entire class were organized around brief patient cases, which were given to the students in advance of the session. During the sessions, each patient case was presented by a physician or pathologist who briefly described symptoms, history, physical findings, differential diagnosis, and the classification of the subtypes of the particular class of disorder. The pathophysiology of the disease was discussed, and the pharmacology of agents to be considered for therapy was presented in the context of the Pharmacology Mental Algorithm, a systematic and rational approach to drug therapy. The session was completed by a clinician who added further clinically relevant information, which was followed by a question-and-answer period involving all faculty participants. The CNS block was presented over a 1-month period and included standardized patients and real patients who consistently exhibited specific disease findings, and these patient-oriented sessions were followed with small group tutorial sessions. Single discipline large-group sessions were also used to present material that is introductory or unique to a particular discipline. Student knowledge was assessed, using integrated evaluations based on case vignettes with multiple-choice questions provided by each discipline. The goal of the examination was to evaluate knowledge base in the discipline areas and its application to clinical problem-solving. A practical evaluation of each student's patient examination skills in CNS was also performed by clinicians. Feedback from the students on the organ system activities was obtained using a questionnaire. Development of these sessions required leadership and a considerable amount of time to organize, improve, and update sessions. The integrated approach largely eliminated the use of conflicting terminology and redundancy of material common with separate presentations on the same subject by different disciplines. The multidisciplinary, case-based sessions were perceived to be instructive, valuable learning experiences, based on formal and informal student and faculty feedback.

Objective Sudden unexpected death in epilepsy (SUDEP) is a rare but devastating consequence of epilepsy and is the leading cause of death in people with epilepsy. SUDEP is associated with certain characteristics such as the presence of generalized tonic–clonic seizures, duration of epilepsy, and refractoriness to anti‐seizure medications. Despite insights from in vivo models, gaps persist in understanding the biological causes of SUDEP, leading to a lack of preventative tools. Current SUDEP preclinical models and data collection and reporting can vary widely across laboratories, hindering the direct translation of findings to humans. Methods The 2020 SUDEP Coalition Summit brought together a team of experts to chart areas of growth and tactics to address these areas. A critical research priority revealed during the summit was the development of data standardization tools to unify SUDEP research efforts. In response, CURE Epilepsy established a Steering Committee to oversee an effort to develop data standardization tools and worked with community members composed of experts in specific domains of SUDEP research to define these tools. Results Experts developed common data elements (CDEs) and case report forms (CRFs) to systematize preclinical SUDEP research. An accompanying publication describes the priority core and death‐related information CRF, while the current work describes supplemental CRFs that SUDEP researchers can use. Specifically, CDEs related to neurological variables, physiologic measures, therapeutics and pharmacology, neuroimaging, ex vivo electrophysiology, and additional phenotypes related to epilepsy are described. Significance Along with the core and death‐related CRF, supplemental CRFs can help the unification of SUDEP research by systematizing various endpoints. Adoption of these data standardization tools can also enhance collaboration between teams, hasten the translatability of SUDEP research to the human condition, and ultimately help prevent SUDEP. Plain Language Summary Preclinical sudden unexpected death in epilepsy (SUDEP) research holds great promise for addressing this fatal condition; however, lack of data standardization remains an issue. Other fields have shown that the incorporation of common data elements (CDEs) can serve to harmonize data across groups, increase rigor, and improve translatability. An accompanying paper describes “Core” CDEs that could be used by all SUDEP preclinical researchers; the current manuscript describes related, supplemental CDEs applicable to researchers depending on their specific scientific question. These include neurological and physiological measures, therapeutics and pharmacology, neuroimaging, ex vivo electrophysiology, and additional phenotypes related to epilepsy.

Objective Sudden Unexpected Death in Epilepsy (SUDEP) is a fatal complication for individuals living with epilepsy and is associated with significant personal and public burden. While certain neurotransmitters and neuronal pathways have been associated with SUDEP, the exact biological mechanisms are unknown. Preclinical research has been instrumental in providing clues to the underlying pathology but is limited by a lack of standardized methodologies for describing and collecting data. A key outcome of the Basic Science working group of the 2020 SUDEP Coalition Summit was the recognition that the development of standardized tools would greatly enhance SUDEP research. Such a research infrastructure would increase experimental rigor, repeatability, reproducibility, and transparency and finally, increase the chances that preclinical SUDEP research can be translated into human SUDEP. Methods CURE Epilepsy assembled a Steering Committee and working groups consisting of experts in preclinical and clinical SUDEP research to develop Common Data Elements (CDEs) and Case Report Forms (CRFs) to enable standardization and translation of preclinical SUDEP data. Standardized methodology from the development of other epilepsy‐related CDEs was used. Results The Core and Death‐Related Information CRF constitutes the priority CRF for SUDEP preclinical studies. This CRF gives investigators CDEs to note details of animal models used, experiment‐related information, and details about triggered and spontaneous seizures. The seizure‐related death information consists of CDEs related to observations at the time of death, characteristics of fatal seizures, the posture of the animal at the time of death, diet, medications, and any adverse health conditions. Significance Systematic use of CDEs and CRFs in SUDEP preclinical research can help increase the rigor and transparency of research. Core CDEs along with supplemental CDEs described in the accompanying manuscript can aid investigators and groups working together toward a common goal of preventing SUDEP. Plain Language Summary Sudden Unexpected Death in Epilepsy (SUDEP) is a fatal complication of epilepsy. Preclinical research holds promise in understanding and preventing SUDEP, but its impacts are limited due to a lack of data standardization and translation among research groups. Common data elements (CDEs) are essential pieces of information for a certain field of study. CURE Epilepsy brought together a team of researchers to develop CDEs that could serve as a blueprint for all SUDEP preclinical researchers. This paper describes the SUDEP Core and Death‐Related CDEs to be used with data elements presented in an accompanying paper.

Penfield and Jasper 1 proposed that generalized seizures involve the brainstem reticular formation (BRF) and other brain sites that are extensively connected to most other brain regions as a centrencephalic system. Considerable subsequent research has confirmed a major role for the BRF in the neuronal networks that subserve generalized convulsive seizure generation. The BRF has been defined to include the core of the brainstem in the medulla, pons, and midbrain. The projections between brainstem nuclei, as well as those to and from the BRF, are massive, including all levels of the central nervous system (CNS) from spinal cord to cerebral cortex. Recent research on the anatomical and neurochemical diversity of nuclei within the BRF has been extensive, leading to a more complex view of the functions of the brainstem. However, these observations have not invalidated the original concept that the BRF has the potential to act as an extremely large network (reticulum) capable of “mass action” under certain circumstances, such as arousal or generalized convulsive seizure. 2–4 Depression of BRF neurons was originally and is still implicated as a major mechanism of action for depressant and anesthetic drugs. 2,5