Functional Neuroimaging as an Assessment Tool in Critically Ill Patients.

OBJECTIVE: Little is known about residual cognitive function in the earliest stages of serious brain injury. Functional neuroimaging has yielded valuable diagnostic and prognostic information in chronic disorders of consciousness, such as the vegetative state (also termed unresponsive wakefulness syndrome). The objective of the current study was to determine if functional neuroimaging could be efficacious in the assessment of cognitive function in acute disorders of consciousness, such as coma, where decisions about the withdrawal of life-sustaining therapies are often made. METHODS: A hierarchical functional magnetic resonance imaging (fMRI) approach assessed sound perception, speech perception, language comprehension, and covert command following in 17 critically ill patients admitted to the intensive care unit (ICU). RESULTS: Preserved auditory function was observed in 15 patients (88%), whereas 5 (29%) also had preserved higher-order language comprehension. Notably, one patient could willfully modulate his brain activity when instructed to do so, suggesting a level of covert conscious awareness that was entirely inconsistent with his clinical diagnosis at the time of the scan. Across patients, a positive relationship was also observed between fMRI responsivity and the level of functional recovery, such that patients with the greatest functional recovery had neural responses most similar to those observed in healthy control participants. INTERPRETATION: These results suggest that fMRI may provide important diagnostic and prognostic information beyond standard clinical assessment in acutely unresponsive patients, which may aid discussions surrounding the continuation or removal of life-sustaining therapies during the early post-injury period. ANN NEUROL 2023;93:131-141.

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.

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.

Disclosing Results of Tests for Covert Consciousness: A Framework for Ethical Translation.

The advent of neurotechnologies including advanced functional magnetic resonance imaging and electroencephalography to detect states of awareness not detectable by traditional bedside neurobehavioral techniques (i.e., covert consciousness) promises to transform neuroscience research and clinical practice for patients with brain injury. As these interventions progress from research tools into actionable, guideline-endorsed clinical tests, ethical guidance for clinicians on how to responsibly communicate the sensitive results they yield is crucial yet remains underdeveloped. Drawing on insights from empirical and theoretical neuroethics research and our clinical experience with advanced neurotechnologies to detect consciousness in behaviorally unresponsive patients, we critically evaluate ethical promises and perils associated with disclosing the results of clinical covert consciousness assessments and describe a semistructured approach to responsible data sharing to mitigate potential risks.

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.

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.

Use of functional magnetic resonance imaging to assess cognition and consciousness in severe Guillain-Barré syndrome.

Objective: Functional neuroimaging may provide a viable means of assessment and communication in patients with Guillain-Barré Syndrome (GBS) mimicking the complete locked-in state. Functional neuroimaging has been used to assess residual cognitive function and has allowed for binary communication with other behaviourally non-responsive patients, such as those diagnosed with unresponsive wakefulness syndrome. We evaluated the potential application of functional neuroimaging using a clinical-grade scanner to determine if individuals with severe GBS retained auditory function, command following, and communication. Methods: Fourteen healthy participants and two GBS patients were asked to perform motor imagery and spatial navigation imagery tasks while being scanned using functional magnetic resonance imaging. The GBS patients were also asked to perform additional functional neuroimaging scans to attempt communication. Results: The motor imagery and spatial navigation task elicited significant activation in appropriate regions of interest for both GBS patients, indicating intact command following. Both patients were able to use the imagery technique to communicate in some instances. Patient 1 was able to use one of four communication tasks to answer a question correctly. Patient 2 was able to use three of seven communication tasks. However, two questions were incorrectly answered while a third was non-verifiable. Conclusions: GBS patients can respond using mental imagery and these responses can be detected using functional neuroimaging. Furthermore, these patients may also be able to use mental imagery to provide answers to 'yes' or 'no' questions in some instances. We argue that the most appropriate use of neuroimaging-based communication in these patients is to allow them to communicate wishes or preferences and assent to previously expressed decisions, rather than to facilitate decision-making.

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.

Triggers for Referral to Specialized Palliative Care in Advanced Neurologic and Neurosurgical Conditions: A Systematic Review.

Background and Objectives: To systematically review the literature for the most suitable trigger criteria for referral to specialist palliative care services in life-limiting and life-threatening neurologic and neurosurgical conditions. Methods: Literature searches were conducted in Ovid MEDLINE and EMBASE (1990-December 2020). To be included, studies must have trigger/referral criteria clearly outlined, a ≥75% nononcology neurosciences population, and consensus or guidelines documents regarding palliative neurosciences or trigger/referral criteria. We excluded studies that had an oncologic or non-neurosciences population as the main focus of study, trigger and referral criteria not clearly outlined, and no primary or duplicative data. The protocol was registered with PROSPERO (CRD4202013579), and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The American Academy of Neurology Clinical Practice Guidelines Process Manual was used to assess for risk of bias. Results: Our search identified 1,748 publications, of which 22 articles met the eligibility criteria. Studies were considered in 2 main groups: (A) studies designed specifically to identify trigger criteria for referral to specialized neuropalliative care services (n = 9) and (B) studies that retrospectively reported the reason for referral to specialized palliative care or reflected a consensus statement among people with advanced neurologic illness (n = 13). Overall, the results suggest that several published referral triggers for specialized neuropalliative care are based on expert consensus. However, there is a growing body of literature providing evidence-based condition-specific triggers for multiple sclerosis, parkinsonism, amyotrophic lateral sclerosis, and dementia. Discussion: There is a growing body of research that outlines evidence-based referral triggers for neuropalliative care. The ambiguity of nomenclature surrounding referral triggers in the current literature and field of neuropalliative care was a limitation to this study. We suggest that condition-specific triggers are likely to be the most effective for identifying the appropriate patients and timing for referral to specialist palliative care. (PROSPERO registration number: CRD42020135791, crd.york.ac.uk/prospero).

Effects of Systemic Physiology on Mapping Resting-State Networks Using Functional Near-Infrared Spectroscopy.

Resting-state functional connectivity (rsFC) has gained popularity mainly due to its simplicity and potential for providing insights into various brain disorders. In this vein, functional near-infrared spectroscopy (fNIRS) is an attractive choice due to its portability, flexibility, and low cost, allowing for bedside imaging of brain function. While promising, fNIRS suffers from non-neural signal contaminations (i.e., systemic physiological noise), which can increase correlation across fNIRS channels, leading to spurious rsFC networks. In the present work, we hypothesized that additional measurements with short channels, heart rate, mean arterial pressure, and end-tidal CO2 could provide a better understanding of the effects of systemic physiology on fNIRS-based resting-state networks. To test our hypothesis, we acquired 12 min of resting-state data from 10 healthy participants. Unlike previous studies, we investigated the efficacy of different pre-processing approaches in extracting resting-state networks. Our results are in agreement with previous studies and reinforce the fact that systemic physiology can overestimate rsFC. We expanded on previous work by showing that removal of systemic physiology decreases intra- and inter-subject variability, increasing the ability to detect neural changes in rsFC across groups and over longitudinal studies. Our results show that by removing systemic physiology, fNIRS can reproduce resting-state networks often reported with functional magnetic resonance imaging (fMRI). Finally, the present work details the effects of systemic physiology and outlines how to remove (or at least ameliorate) their contributions to fNIRS signals acquired at rest.

How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries.

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES.

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.

Loss of Cntnap2 in the Rat Causes Autism-Related Alterations in Social Interactions, Stereotypic Behavior, and Sensory Processing.

Autism spectrum disorder (ASD) is characterized by social interaction and communication impairments, as well as restrictive/repetitive patterns of behavior, interests or activities, which can coexist with intellectual disability and altered sensory processing. To study the mechanisms underlying these core features of ASD, preclinical research has developed animal models with manipulations in ASD-linked genes, such as CNTNAP2. In order to fully interpret the findings from mechanistic studies, the extent to which these models display behaviors consistent with ASD must be determined. Toward that goal, we conducted an investigation of the consequences of a functional loss of Cntnap2 on ASD-related behaviors by comparing the performance of rats with a homozygous or heterozygous knockout of Cntnap2 to their wildtype littermates across a comprehensive test battery. Cntnap2-/- rats showed deficits in sociability and social novelty, and they displayed repetitive circling and hyperlocomotion. Moreover, Cntnap2-/- rats demonstrated exaggerated acoustic startle responses, increased avoidance to sounds of moderate intensity, and a lack of rapid audiovisual temporal recalibration; indicating changes in sensory processing at both the pre-attentive and perceptual levels. Notably, sensory behaviors requiring learned associations did not reveal genotypic differences, whereas tasks relying on automatic/implicit behaviors did. Ultimately, because these collective alterations in social, stereotypic, and sensory behaviors are phenotypically similar to those reported in individuals with ASD, our results establish the Cntnap2 knockout rat model as an effective platform to study not only the molecular and cellular mechanisms associated with ASD, but also the complex relationship between altered sensory processing and other core ASD-related behaviors. LAY SUMMARY: Autism spectrum disorder (ASD) is characterized by social interaction differences, and restrictive/repetitive patterns of behavior. We studied the behavioral alterations caused by the loss of an autism-linked gene, Cntnap2, in the rat to determine how mutations in this gene contribute to autism-related behaviors. We show the loss of Cntnap2 leads to changes in social, stereotypic, and sensory behaviors, indicating this rat model can be used to better understand the brain changes underlying ASD. Autism Res 2020, 13: 1698-1717. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Use of functional magnetic resonance imaging to assess cognition and consciousness in severe Guillain-Barré syndrome

Objective: Functional neuroimaging may provide a viable means of assessment and communication in patients with Guillain-Barré Syndrome (GBS) mimicking the complete locked-in state. Functional neuroimaging has been used to assess residual cognitive function and has allowed for binary communication with other behaviourally non-responsive patients, such as those diagnosed with unresponsive wakefulness syndrome. We evaluated the potential application of functional neuroimaging using a clinical-grade scanner to determine if individuals with severe GBS retained auditory function, command following, and communication. Methods: Fourteen healthy participants and two GBS patients were asked to perform motor imagery and spatial navigation imagery tasks while being scanned using functional magnetic resonance imaging. The GBS patients were also asked to perform additional functional neuroimaging scans to attempt communication. Results: The motor imagery and spatial navigation task elicited significant activation in appropriate regions of interest for both GBS patients, indicating intact command following. Both patients were able to use the imagery technique to communicate in some instances. Patient 1 was able to use one of four communication tasks to answer a question correctly. Patient 2 was able to use three of seven communication tasks. However, two questions were incorrectly answered while a third was non-verifiable. Conclusions: GBS patients can respond using mental imagery and these responses can be detected using functional neuroimaging. Furthermore, these patients may also be able to use mental imagery to provide answers to ‘yes’ or ‘no’ questions in some instances. We argue that the most appropriate use of neuroimaging-based communication in these patients is to allow them to communicate wishes or preferences and assent to previously expressed decisions, rather than to facilitate decision-making. (AU)