Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Predicting neurologic recovery after severe acute brain injury using resting-state networks.

OBJECTIVE: There is a lack of reliable tools used to predict functional recovery in unresponsive patients following a severe brain injury. The objective of the study is to evaluate the prognostic utility of resting-state functional magnetic resonance imaging for predicting good neurologic recovery in unresponsive patients with severe brain injury in the intensive-care unit. METHODS: Each patient underwent a 5.5-min resting-state scan and ten resting-state networks were extracted via independent component analysis. The Glasgow Outcome Scale was used to classify patients into good and poor outcome groups. The Nearest Centroid classifier used each patient's ten resting-state network values to predict best neurologic outcome within 6 months post-injury. RESULTS: Of the 25 patients enrolled (mean age = 43.68, range = [19-69]; GCS ≤ 9; 6 females), 10 had good and 15 had poor outcome. The classifier correctly and confidently predicted 8/10 patients with good and 12/15 patients with poor outcome (mean = 0.793, CI = [0.700, 0.886], Z = 2.843, p = 0.002). The prediction performance was largely determined by three visual (medial: Z = 3.11, p = 0.002; occipital pole: Z = 2.44, p = 0.015; lateral: Z = 2.85, p = 0.004) and the left frontoparietal network (Z = 2.179, p = 0.029). DISCUSSION: Our approach correctly identified good functional outcome with higher sensitivity (80%) than traditional prognostic measures. By revealing preserved networks in the absence of discernible behavioral signs, functional connectivity may aid in the prognostic process and affect the outcome of discussions surrounding withdrawal of life-sustaining measures.

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline.

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists' Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.

RéSUMé: Ces Lignes directrices de pratique clinique 2023 Lignes directrices de pratique clinique dicale du décès basée sur l'arrêt permanent de la fonction cérébrale qui s'applique à toute personne, ainsi que des recommandations pour la détermination du décès par des critères circulatoires pour des donneurs d'organes potentiels et des recommandations pour la détermination du décès par des critères neurologiques pour tous les patients sous ventilation mécanique, indépendamment de leur potentiel de donneur d'organes. Les présentes Lignes directrices sont approuvées par la Société canadienne de soins intensifs, l'Association médicale canadienne, l'Association canadienne des infirmiers/infirmières en soins intensifs, la Société canadienne des anesthésiologistes, la Fédération des sciences neurologiques du Canada (représentant la Société canadienne de neurologie, la Société canadienne de neurochirurgie, la Société canadienne de neurophysiologie clinique, l'Association canadienne de neurologie pédiatrique, la Société canadienne de neuroradiologie et le Consortium neurovasculaire canadien), la Société canadienne du sang, le Programme de recherche en don et transplantation du Canada, l'Association canadienne des médecins d'urgence, l'Association des infirmières et infirmiers praticiens du Canada, et la Société canadienne de soins intensifs cardiovasculaires (CANCARE) et la Société canadienne de pédiatrie.

The seasonality of new-onset refractory status epilepticus (NORSE).

The etiology of new-onset refractory status epilepticus (NORSE), including its subtype with prior fever known as FIRES (febrile infection-related epilepsy syndrome), remains uncertain. Several arguments suggest that NORSE is a disorder of immunity, likely post-infectious. Consequently, seasonal occurrence might be anticipated. Herein we investigated if seasonality is a notable factor regarding NORSE presentation. We combined four different data sets with a total of 342 cases, all from the northern hemisphere, and 62% adults. The incidence of NORSE cases differed between seasons (p = .0068) and was highest in the summer (32.2%) (p = .0022) and lowest in the spring (19.0%, p = .010). Although both FIRES and non-FIRES cases occurred most commonly during the summer, there was a trend toward FIRES cases being more likely to occur in the winter than non-FIRES cases (OR 1.62, p = .071). The seasonality of NORSE cases differed according to the etiology (p = .024). NORSE cases eventually associated with autoimmune/paraneoplastic encephalitis occurred most frequently in the summer (p = .032) and least frequently in the winter (p = .047), whereas there was no seasonality for cryptogenic cases. This study suggests that NORSE overall and NORSE related to autoimmune/paraneoplastic encephalitis are more common in the summer, but that there is no definite seasonality in cryptogenic cases.

Clinical milestones as triggers for palliative care intervention in progressive Supranuclear palsy and multiple system atrophy.

not required for reviews.

Trainee Distress When Faced with End-of-Life Care in Neurology: A Qualitative Analysis.

OBJECTIVE: To identify sources of distress experienced by trainees when providing neuropalliative care and to explore the perceived and unperceived educational needs of trainees learning to deliver neuropalliative care. METHOD: This study is a post hoc analysis of a qualitative investigation performed at a single Canadian academic center with active clinical services in palliative medicine, neurology, and neurosurgery. Grounded theory methodology was used to explore trainees' perspectives when learning neuropalliative care. This study used focus groups, using open-ended questions, to elicit participants' experiences providing neuropalliative care as well as to explore the challenges in neuropalliative care. RESULTS: Qualitative analysis identified multiple sources of distress for trainees in neuropalliative care and broad themes emerged: 1) a lack of experience and knowledge, 2) the emotional toll of learning neuropalliative care, and 3) prognostic uncertainty in neuropalliative care. CONCLUSION: Our results suggest that palliative neurology curricula should focus not only on symptom management but also on strategies for improving communication about prognosis and managing clinical uncertainty. Improving trainee comfort and confidence in neuropalliative care throughout the illness trajectory may alleviate sources of distress during training and increase quality of care.

When to initiate palliative care in neurology.

Life-limiting and life-threatening neurologic conditions often progress slowly. Patients live with a substantial symptom burden over a long period of time, and there is often a high degree of functional and cognitive impairment. Because of this, the most appropriate time to initiate neuropalliative care is often difficult to identify. Further challenges to the incorporation of neuropalliative care include communication barriers, such as profound dysarthria or language impairments, and loss of cognitive function and decision-making capacity that prevent shared decision making and threaten patient autonomy. As a result, earlier initiation of at least some components of palliative care is paramount to ensuring patient-centered care while the patient is still able to communicate effectively and participate as fully as possible in their medical care. For these reasons, neuropalliative care is also distinct from palliative care in oncology, and there is a growing evidence base to guide timely initiation and integration of neuropalliative care. In this chapter, we will focus on when to initiate palliative care in patients with life-limiting, life-threatening, and advanced neurologic conditions. We will address three main questions, which patients with neurologic conditions will benefit from initiation of palliative care, what aspects of neurologic illness are most amenable to neuropalliative care, and when to initiate neuropalliative care?

Cerebral cortical activity after withdrawal of life-sustaining measures in critically ill patients.

Establishing when cerebral cortical activity stops relative to circulatory arrest during the dying process will enhance trust in donation after circulatory determination of death. We used continuous electroencephalography and arterial blood pressure monitoring prior to withdrawal of life sustaining measures and for 30 min following circulatory arrest to explore the temporal relationship between cessation of cerebral cortical activity and circulatory arrest. Qualitative and quantitative EEG analyses were completed. Among 140 screened patients, 52 were eligible, 15 were enrolled, 11 completed the full study, and 8 (3 female, median age 68 years) were included in the analysis. Across participants, EEG activity stopped at a median of 78 (Q1 = -387, Q3 = 111) seconds before circulatory arrest. Following withdrawal of life sustaining measures there was a progressive reduction in electroencephalographic amplitude (p = .002), spectral power (p = .008), and coherence (p = .003). Prospective recording of cerebral cortical activity in imminently dying patients is feasible. Our results from this small cohort suggest that cerebral cortical activity does not persist after circulatory arrest. Confirmation of these findings in a larger multicenter study are needed to help promote stakeholder trust in donation after circulatory determination of death.

Improving Diagnosis and Prognosis in Acute Severe Brain Injury: A Multimodal Imaging Protocol.

Multi-modal neuroimaging techniques have the potential to dramatically improve the diagnosis of the level consciousness and prognostication of neurological outcome for patients with severe brain injury in the intensive care unit (ICU). This protocol describes a study that will utilize functional Magnetic Resonance Imaging (fMRI), electroencephalography (EEG), and functional Near Infrared Spectroscopy (fNIRS) to measure and map the brain activity of acute critically ill patients. Our goal is to investigate whether these modalities can provide objective and quantifiable indicators of good neurological outcome and reliably detect conscious awareness. To this end, we will conduct a prospective longitudinal cohort study to validate the prognostic and diagnostic utility of neuroimaging techniques in the ICU. We will recruit 350 individuals from two ICUs over the course of 7 years. Participants will undergo fMRI, EEG, and fNIRS testing several times over the first 10 days of care to assess for residual cognitive function and evidence of covert awareness. Patients who regain behavioral awareness will be asked to complete web-based neurocognitive tests for 1 year, as well as return for follow up neuroimaging to determine which acute imaging features are most predictive of cognitive and functional recovery. Ultimately, multi-modal neuroimaging techniques may improve the clinical assessments of patients' level of consciousness, aid in the prediction of outcome, and facilitate efforts to find interventional methods that improve recovery and quality of life.

Cortical Function in Acute Severe Traumatic Brain Injury and at Recovery: A Longitudinal fMRI Case Study.

Differences in the functional integrity of the brain from acute severe brain injury to subsequent recovery of consciousness have not been well documented. Functional magnetic resonance imaging (fMRI) may elucidate this issue as it allows for the objective measurement of brain function both at rest and in response to stimuli. Here, we report the cortical function of a patient with a severe traumatic brain injury (TBI) in a critically ill state and at subsequent functional recovery 9-months post injury. A series of fMRI paradigms were employed to assess sound and speech perception, command following, and resting state connectivity. The patient retained sound perception and speech perception acutely, as indexed by his fMRI responses. Command following was absent acutely, but was present at recovery. Increases in functional connectivity across multiple resting state networks were observed at recovery. We demonstrate the clinical utility of fMRI in assessing cortical function in a patient with severe TBI. We suggest that hallmarks of the recovery of consciousness are associated with neural activity to higher-order cognitive tasks and increased resting state connectivity.

Stroke risk, phenotypes, and death in COVID-19: Systematic review and newly reported cases.

OBJECTIVES: To investigate the hypothesis that strokes occurring in patients with coronavirus disease 2019 (COVID-19) have distinctive features, we investigated stroke risk, clinical phenotypes, and outcomes in this population. METHODS: We performed a systematic search resulting in 10 studies reporting stroke frequency among patients with COVID-19, which were pooled with 1 unpublished series from Canada. We applied random-effects meta-analyses to estimate the proportion of stroke among COVID-19. We performed an additional systematic search for cases series of stroke in patients with COVID-19 (n = 125), and we pooled these data with 35 unpublished cases from Canada, the United States, and Iran. We analyzed clinical characteristics and in-hospital mortality stratified into age groups (<50, 50-70, >70 years). We applied cluster analyses to identify specific clinical phenotypes and their relationship with death. RESULTS: The proportions of patients with COVID-19 with stroke (1.8%, 95% confidence interval [CI] 0.9%-3.7%) and in-hospital mortality (34.4%, 95% CI 27.2%-42.4%) were exceedingly high. Mortality was 67% lower in patients <50 years of age relative to those >70 years of age (odds ratio [OR] 0.33, 95% CI 0.12-0.94, p = 0.039). Large vessel occlusion was twice as frequent (46.9%) as previously reported and was high across all age groups, even in the absence of risk factors or comorbid conditions. A clinical phenotype characterized by older age, a higher burden of comorbid conditions, and severe COVID-19 respiratory symptoms was associated with the highest in-hospital mortality (58.6%) and a 3 times higher risk of death than the rest of the cohort (OR 3.52, 95% CI 1.53-8.09, p = 0.003). CONCLUSIONS: Stroke is relatively frequent among patients with COVID-19 and has devastating consequences across all ages. The interplay of older age, comorbid conditions, and severity of COVID-19 respiratory symptoms is associated with an extremely elevated mortality.

A Pilot Cross-Discipline Evidence-Based Palliative Care Curriculum for Postgraduate Medical Trainees.

INTRODUCTION: It is widely recognized that physicians of all backgrounds benefit from having a general palliative care skill set to optimally manage their patients at the end of life. However, strategies to teach palliative care skills to trainees outside palliative medicine vary widely. In this report, we provide an evidence-based and cross-disciplinary palliative care framework applicable to a spectrum of specialty training environments and intended for nonpalliative care trainees. INNOVATION: We developed and implemented a concise, multimodal, and evidence-based pilot palliative care curriculum focused on essential general palliative care skills required by physicians providing patient care along the continuum of life across specializations. A needs assessment (local research, literature review, and consensus expert opinion) in combination with learner characteristics (Kolb Learning Style Inventory, Palliative Medicine Comfort and Confidence Survey, and knowledge pretest) informed the development of a curricular outline. The first iteration of the curriculum was formulated and delivered. Extensive evaluation, reassessment, and feedback led to a second iteration, which is presented here. OUTCOMES: Although the context will differ according to specialization, there are essential palliative care skills required of most specialist physicians. General palliative themes identified for focus include symptom management, communication, psychosocial aspects of care, care coordination and access, and myths and pitfalls in palliative care. COMMENT: Specialty trainees' value embedded training in essential themes in palliative care within the context of their training program. The process and results of this project, including the provision of a framework, may be applied to postgraduate training programs in various specialties.

Addressing the competency of breaking bad news: What are Canadian general paediatric residency programs currently doing.

OBJECTIVE: To describe how breaking bad news (BBN) is currently taught in Canadian general paediatric residency programs and the confidence level of fourth year paediatric residents (Ped-PGY4) in BBN and managing end-of-life-care (EOLC). METHODS: A prospective, cross-sectional survey of General Paediatric Residency Program Directors (PDs) and Ped-PGY4s was conducted. RESULTS: When learning to BBN, residents state faculty observation (22/23) and interactive workshops (14/23) are the most helpful, while PDs state interactive workshops (9/16) and deliberate practice (5/16) are ideal. Residents identified a knowledge gap and discomfort with providing anticipatory guidance, and symptom management, including prescribing opioids. CONCLUSIONS: In the era of competency-based medical education, there is an opportunity to create a standardized national curriculum addressing universal competencies related to BBN and EOLC.

Communication Challenges: A Spotlight on New-Onset Refractory Status Epilepticus.

New-onset refractory status epilepticus (NORSE) is a rare, potentially devastating condition that occurs abruptly in previously healthy patients of any age but most commonly in children and young adults. It has an unpredictable clinical course requiring immediate, often prolonged, critical care support with multiple specialists involved and frequently results in severe life-altering sequelae or death. Communication in NORSE is challenging because its etiology in a given patient is initially unknown (and often remains so), the clinical course and outcome are unpredictable, and many health care team members are involved in the care of a patient. We address the communication challenges seen in NORSE through proactive communication on 3 levels: (1) in the shared decision-making process with the family, (2) within an individual hospital, and (3) across institutions. Intentional organizational change and enhanced information dissemination may help break down barriers to effective communication. Key initiatives for enhancing information dissemination in NORSE are (1) the identification of a most responsible physician to integrate information from subspecialties, to communicate frequently and candidly with the family, and to provide continuity of care over a prolonged period of time and (2) the early involvement of palliative care services alongside ongoing therapies with curative intent to support families and the medical team in decision making and communication.

New onset refractory status epilepticus research: What is on the horizon?

New-onset refractory status epilepticus (NORSE) is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurologic disorder, with new onset of refractory status epilepticus (RSE) that does not resolve after 2 or more rescue medications, without a clear acute or active structural, toxic, or metabolic cause. Febrile infection-related epilepsy syndrome is a subset of NORSE in which fever began at least 24 hours prior to the RSE. Both terms apply to all age groups. Until recently, NORSE was a poorly recognized entity without a consistent definition or approach to care. We review the current state of knowledge in NORSE and propose a roadmap for future collaborative research. Research investigating NORSE should prioritize the following 4 domains: (1) clinical features, etiology, and pathophysiology; (2) treatment; (3) adult and pediatric evaluation and management approaches; and (4) public advocacy, professional education, and family support. We consider international collaboration and multicenter research crucial in achieving these goals.

Patterns of Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis.

BACKGROUND: Non-invasive ventilation (NIV) improves quality of life and survival in patients with amyotrophic lateral sclerosis (ALS) and respiratory symptoms. Little is known about the patterns of NIV use over time and the impact of NIV on end-of-life decision-making in ALS. OBJECTIVE: This study assessed the pattern of NIV use over the course of the disease and the timing of end-of-life discussions in people living with ALS. METHOD: A retrospective single-center cohort study was performed at London Health Sciences Centre. Daily NIV duration of use was evaluated at 3-month intervals. The timing of diagnosis, NIV initiation, discussions relating to do-not-attempt-resuscitation (DNAR) and death were examined. RESULTS: In total, 48 patients were included in the analysis. Duration of NIV use increased over time, and tolerance to NIV was observed to be better than expected in patients with bulbar-onset ALS. There was a high degree of variability in the timing of end-of-life discussions in patients with ALS (356±451 days from diagnosis). In this cohort, there was a strong association between the timing of discussions regarding code status and establishment of a DNAR order (r2=0.93). CONCLUSION: This retrospective cohort study suggests that the use of NIV in ALS increases over time and that there remains a great deal of variability in the timing of end-of-life discussions in people living with ALS. Future prospective studies exploring the use NIV over the disease trajectory and how NIV affects end-of-life decision-making in people with ALS are needed.