Long-Term Cognitive Outcome in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: Cognitive dysfunction is a core symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long-term outcome and identify clinical predictors. METHODS: Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. RESULTS: All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale = 1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. INTERPRETATION: Cognitive deficits are the main contributor to long-term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies. ANN NEUROL 2021;90:949-961.

Automated Assessment of Brain CT After Cardiac Arrest-An Observational Derivation/Validation Cohort Study.

OBJECTIVES: Prognostication of outcome is an essential step in defining therapeutic goals after cardiac arrest. Gray-white-matter ratio obtained from brain CT can predict poor outcome. However, manual placement of regions of interest is a potential source of error and interrater variability. Our objective was to assess the performance of poor outcome prediction by automated quantification of changes in brain CTs after cardiac arrest. DESIGN: Observational, derivation/validation cohort study design. Outcome was determined using the Cerebral Performance Category upon hospital discharge. Poor outcome was defined as death or unresponsive wakefulness syndrome/coma. CTs were automatically decomposed using coregistration with a brain atlas. SETTING: ICUs at a large, academic hospital with circulatory arrest center. PATIENTS: We identified 433 cardiac arrest patients from a large previously established database with brain CTs within 10 days after cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Five hundred sixteen brain CTs were evaluated (derivation cohort n = 309, validation cohort n = 207). Patients with poor outcome had significantly lower radiodensities in gray matter regions. Automated GWR_si (putamen/posterior limb of internal capsule) was performed with an area under the curve of 0.86 (95%-CI: 0.80-0.93) for CTs taken later than 24 hours after cardiac arrest (similar performance in the validation cohort). Poor outcome (Cerebral Performance Category 4-5) was predicted with a specificity of 100% (95% CI, 87-100%, derivation; 88-100%, validation) at a threshold of less than 1.10 and a sensitivity of 49% (95% CI, 36-58%, derivation) and 38% (95% CI, 27-50%, validation) for CTs later than 24 hours after cardiac arrest. Sensitivity and area under the curve were lower for CTs performed within 24 hours after cardiac arrest. CONCLUSIONS: Automated gray-white-matter ratio from brain CT is a promising tool for prediction of poor neurologic outcome after cardiac arrest with high specificity and low-to-moderate sensitivity. Prediction by gray-white-matter ratio at the basal ganglia level performed best. Sensitivity increased considerably for CTs performed later than 24 hours after cardiac arrest.

Disentangling Hippocampal and Amygdala Contribution to Human Anxiety-Like Behavior.

Anxiety comprises a suite of behaviors to deal with potential threat and is often modeled in approach-avoidance conflict tasks. Collectively, these tests constitute a predominant preclinical model of anxiety disorder. A body of evidence suggests that both ventral hippocampus and amygdala lesions impair anxiety-like behavior, but the relative contribution of these two structures is unclear. A possible reason is that approach-avoidance conflict tasks involve a series of decisions and actions, which may be controlled by distinct neural mechanisms that are difficult to disentangle from behavioral readouts. Here, we capitalize on a human approach-avoidance conflict test, implemented as computer game, that separately measures several action components. We investigate three patients of both sexes with unspecific unilateral medial temporal lobe (MTL) damage, one male with selective bilateral hippocampal (HC), and one female with selective bilateral amygdala lesions, and compare them to matched controls. MTL and selective HC lesions, but not selective amygdala lesions, increased approach decision when possible loss was high. In contrast, MTL and selective amygdala lesions, but not selective HC lesions, increased return latency. Additionally, selective HC and selective amygdala lesions reduced approach latency. In a task targeted at revealing subjective assumptions about the structure of the computer game, MTL and selective HC lesions impacted on reaction time generation but not on the subjective task structure. We conclude that deciding to approach reward under threat relies on hippocampus but not amygdala, whereas vigor of returning to safety depends on amygdala but not on hippocampus.SIGNIFICANCE STATEMENT Approach-avoidance conflict tests are widely investigated in rodents, and increasingly in humans, to understand the neural basis of anxiety-like behavior. However, the contribution of the most relevant brain regions, ventral hippocampus and amygdala, is incompletely understood. We use a human computerized test that separates different action components and find that hippocampus, but not amygdala, lesions impair approach decisions, whereas amygdala, but not hippocampus, lesions impair the vigor of return to safety.

Early volumetric changes of hippocampus and medial prefrontal cortex following medial temporal lobe resection.

Previous studies have shown that cognitive demands and physical exercise stimulate adult neurogenesis in the dentate gyrus and hippocampus. Recent observations in healthy humans and patients with mild cognitive impairment moreover suggest that training-induced increases in hippocampal volume may be associated with improved memory performance. The corresponding plasticity processes in hippocampal volume may occur on timescales of months to years. For patients with focal lesions in this region, previous functional imaging studies suggest that increased recruitment of the contralateral hippocampus and extratemporal regions may be an important part of the reorganization of episodic memory. However, it is currently unclear whether focal damage to the medial temporal lobe (MTL) induces gray matter (GM) volume changes in the intact contralateral hippocampus and in connected network regions on a shorter timescale. We therefore investigated whether unilateral resection of the MTL, including the hippocampus, induces measurable volumetric changes in the contralateral hippocampus and in the default mode network (DMN). We recruited 31 patients with unilateral left (N = 19) or right (N = 12) hippocampal sclerosis undergoing MTL resection for treatment of drug-resistant epilepsy. Structural MRI was acquired immediately before and 3 months after surgery. Longitudinal voxel-based morphometry (VBM) analysis revealed a significant increase of right hippocampal volume following resection of the left anterior MTL. Furthermore, this patient group showed GM volume increases in the DMN. These results demonstrate significant structural plasticity of the contralateral hippocampus, even in patients with a long-standing unilateral hippocampal dysfunction and structural reorganization processes extending to distant, but functionally connected brain regions.

Superficial white matter damage in anti-NMDA receptor encephalitis.

BACKGROUND: Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter. METHODS: Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity. RESULTS: Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients. CONCLUSIONS: Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

Memory integration in humans with hippocampal lesions.

Adaptive behavior frequently depends on inference from past experience. Recent studies suggest that the underlying process of integrating related memories may depend on interaction between hippocampus and prefrontal cortex. Here, we investigated how hippocampal damage affects memory integration. Subjects with mediotemporal lesions and healthy controls learned a set of overlapping AB- and BC-associations (object-face- and face-object pairs) and were then tested for memory of these associations ("direct" trials) and of inferential AC-associations ("indirect" trials). The experiment consisted of four encoding/retrieval cycles. In direct trials, performance of patients and controls was similar and stable across cycles. By contrast, in indirect trials, patients and controls showed distinct patterns of behavior. Whereas patients and controls initially showed only minor differences, controls increased performance across subsequent cycles, while patient performance decreased to chance level. Further analysis suggested that this deficit was not merely a consequence of impaired associative memory but rather resulted from an additional hippocampal contribution to memory integration. Our findings further suggest that contextual factors modulate this contribution. Patient deficits in more complex memory-guided behavior may depend on the flexible interaction of hippocampus-dependent and -independent mechanisms of memory integration.

Neuron-Specific Enolase Predicts Poor Outcome After Cardiac Arrest and Targeted Temperature Management: A Multicenter Study on 1,053 Patients.

OBJECTIVE: Outcome prediction after cardiac arrest is important to decide on continuation or withdrawal of intensive care. Neuron-specific enolase is an easily available, observer-independent prognostic biomarker. Recent studies have yielded conflicting results on its prognostic value after targeted temperature management. DESIGN, SETTING, AND PATIENTS: We analyzed neuron-specific enolase serum concentrations 3 days after nontraumatic in-hospital cardiac arrest and out-of-hospital cardiac arrest and outcome of patients from five hospitals in Germany, Austria, and Italy. Patients were treated at 33°C for 24 hours. Cerebral Performance Category was evaluated upon ICU discharge. We performed case reviews of good outcome patients with neuron-specific enolase greater than 90 µg/L and poor outcome patients with neuron-specific enolase less than or equal to 17 µg/L (upper limit of normal). MEASUREMENTS AND MAIN RESULTS: A neuron-specific enolase serum concentration greater than 90 µg/L predicted Cerebral Performance Category 4-5 with a positive predictive value of 99%, false positive rate of 0.5%, and a sensitivity of 48%. All three patients with neuron-specific enolase greater than 90 µg/L and Cerebral Performance Category 1-2 had confounders for neuron-specific enolase elevation. An neuron-specific enolase serum concentration less than or equal to 17 µg/L excluded Cerebral Performance Category 4-5 with a negative predictive value of 92%. The majority of 14 patients with neuron-specific enolase less than or equal to 17 µg/L who died had a cause of death other than hypoxic-ischemic encephalopathy. Specificity and sensitivity for prediction of poor outcome were independent of age, sex, and initial rhythm but higher for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. CONCLUSION: High neuron-specific enolase serum concentrations reliably predicted poor outcome at ICU discharge. Prediction accuracy differed and was better for out-of-hospital cardiac arrest than for in-hospital cardiac arrest patients. Our "in-the-field" data indicate 90 µg/L as a threshold associated with almost no false positives at acceptable sensitivity. Confounders of neuron-specific enolase elevation should be actively considered: neuron-specific enolase-producing tumors, acute brain diseases, and hemolysis. We strongly recommend routine hemolysis quantification. Neuron-specific enolase serum concentrations less than or equal to 17 µg/L argue against hypoxic-ischemic encephalopathy incompatible with reawakening.

Neural correlates of short-term memory reorganization in humans with hippocampal damage.

Some patients with disorders affecting the hippocampus have relatively intact memory, but the mechanisms underlying this preservation of function are still debated. In particular, it is unclear whether preserved memory is attributable to significant residual function of unaffected hippocampus or to functional brain reorganization. Here, we investigated brain activation during an associative short-term memory task in two human patient groups matched for extent of postsurgical damage to the right hippocampal formation that differed in two key features, memory performance and preoperative disease course. Patients showed strikingly distinct activation patterns that correlated differentially with behavioral performance, strongly suggesting that intact associative short-term memory with hippocampal dysfunction is indeed related to compensatory brain reorganization. This process appears to depend both on activation of the contralesional hippocampus and on increased engagement of a distributed short-term memory network in neocortex. These data clarify the existence of an efficient hippocampal-neocortical mechanism that compensates for hippocampal dysfunction.

Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.

Memory consolidation affects the interplay of place and response navigation.

Navigation through space is based on memory representations of landmarks ('place') or movement sequences ('response'). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation.

Survival, but not the severity of hypoxic-ischemic encephalopathy, is associated with higher mean arterial blood pressure after cardiac arrest: a retrospective cohort study.

Background: This study investigates the association between the mean arterial blood pressure (MAP), vasopressor requirement, and severity of hypoxic-ischemic encephalopathy (HIE) after cardiac arrest (CA). Methods: Between 2008 and 2017, we retrospectively analyzed the MAP 200 h after CA and quantified the vasopressor requirements using the cumulative vasopressor index (CVI). Through a postmortem brain autopsy in non-survivors, the severity of the HIE was histopathologically dichotomized into no/mild and severe HIE. In survivors, we dichotomized the severity of HIE into no/mild cerebral performance category (CPC) 1 and severe HIE (CPC 4). We investigated the regain of consciousness, causes of death, and 5-day survival as hemodynamic confounders. Results: Among the 350 non-survivors, 117 had histopathologically severe HIE while 233 had no/mild HIE, without differences observed in the MAP (73.1 vs. 72.0 mmHg, pgroup = 0.639). Compared to the non-survivors, 211 patients with CPC 1 and 57 patients with CPC 4 had higher MAP values that showed significant, but clinically non-relevant, MAP differences (81.2 vs. 82.3 mmHg, pgroup < 0.001). The no/mild HIE non-survivors (n = 54), who regained consciousness before death, had higher MAP values compared to those with no/mild HIE (n = 179), who remained persistently comatose (74.7 vs. 69.3 mmHg, pgroup < 0.001). The no/mild HIE non-survivors, who regained consciousness, required fewer vasopressors (CVI 2.1 vs. 3.6, pgroup < 0.001). Independent of the severity of HIE, the survivors were weaned faster from vasopressors (CVI 1.0). Conclusions: Although a higher MAP was associated with survival in CA patients treated with a vasopressor-supported MAP target above 65 mmHg, the severity of HIE was not. Awakening from coma was associated with less vasopressor requirements. Our results provide no evidence for a MAP target above the current guideline recommendations that can decrease the severity of HIE.

N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis.

OBJECTIVE: To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE). METHODS: Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients' serum was studied in cultures of primary mouse hippocampal neurons. RESULTS: N-Methyl-D-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons. INTERPRETATION: Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy. .

Theta-burst stimulation over human frontal cortex distorts perceptual stability across eye movements.

We perceive a stable outside world despite the constant changes of visual input induced by our eye movements. Internal monitoring of a corollary discharge associated with oculomotor commands may help to anticipate the perceptual consequences of impending eye movements. The primate frontal eye fields have repeatedly been presumed to participate in the maintenance of perceptual stability across eye movements. However, a direct link between integrity of frontal oculomotor areas and perceptual stability is missing so far. Here, we show that transcranial magnetic stimulation (TMS) over the right human frontal cortex impairs the integration of visual space across eye movements. We asked 9 healthy subjects to report the direction of transsaccadic stimulus displacements and applied TMS before the actual experiment in a novel offline stimulation protocol, continuous theta-burst stimulation (cTBS). A systematic perceptual distortion was observed after stimulation over the right frontal cortex that was best explained by an internal underestimation of executed eye movement amplitudes. cTBS apparently disturbed an internal prediction process for contraversive saccades, while the metrics of associated oculomotor actions remained unchanged. Our findings suggest an important role of the frontal cortex in the internal monitoring of oculomotor actions for the perceptual integration of space across eye movements.

Human thalamus contributes to perceptual stability across eye movements.

We continuously move our eyes when we inspect a visual scene. Although this leads to a rapid succession of discontinuous and fragmented retinal snapshots, we perceive the world as stable and coherent. Neural mechanisms underlying visual stability may depend on internal monitoring of planned or ongoing eye movements. In the macaque brain, a pathway for the transmission of such signals has been identified that is relayed by central thalamic nuclei. Here, we studied a possible role of this pathway for perceptual stability in a patient with a selective lesion affecting homologous regions of the human thalamus. Compared with controls, the patient exhibited a unilateral deficit in monitoring his eye movements. This deficit was manifest by a systematic inaccuracy both in successive eye movements and in judging the locations of visual stimuli. In addition, perceptual consequences of oculomotor targeting errors were erroneously attributed to external stimulus changes. These findings show that the human brain draws on transthalamic monitoring signals to bridge the perceptual discontinuities generated by our eye movements.

Improvement of door-to-imaging time in acute stroke patients by implementation of an all-points alarm.

In patients with acute ischemic stroke, thrombolysis offers an opportunity to effectively reduce disability and dependency. The success of this treatment is time-dependent. The crucial diagnostic step before initiation of treatment is cerebral imaging. With the aim of reducing in-hospital delays, our hospital's interdisciplinary stroke management group implemented an all-points alarm to improve in-hospital time delay (the period between arrival to the emergency department and performance of cerebral imaging). The alarm simultaneously alerted all involved staff (from the neurologist to in-hospital transport) to the arrival of a patient potentially eligible for thrombolysis. Time delay, sociodemographic, and clinical data were assessed prospectively at 4 months before and 8 months after alarm implementation. Data were examined by analysis of covariance for both the intention-to-treat and per-protocol groups. During the assessment, 689 patients with symptoms compatible with stroke arrived at our hospital. Among those, 111 patients (16%) were eligible for thrombolysis (median age, 71 years; median National Institutes of Health Stroke Scale score, 11; 44% female). Patient characteristics (ie, age, sex, insurance status, National Institutes of Health Stroke Scale score, cardiovascular risk factors, and prehospital delay) did not differ significantly before (n = 34) and after (n = 77) alarm implementation. The median "door-to-imaging time" for patients eligible for thrombolysis was significantly reduced, from 54 minutes before implementation of the alarm to 35 minutes after implementation. Adjusted analysis of covariance demonstrated a significant influence of the intervention (P = .001) on differences in time delay. The proportion of ischemic stroke patients receiving thrombolysis rose from 42% to 66% (P = .04). The per-protocol analysis confirmed these results. The implementation of an all-points alarm can result in significant reduction of the time needed for in-hospital pathways for acute stroke patients.

Memory-guided navigation in amyotrophic lateral sclerosis.

BACKGROUND: Previous studies have yielded inconsistent results about hippocampal involvement in non-demented patients with amyotrophic lateral sclerosis (ALS). We hypothesized that testing of memory-guided spatial navigation i.e., a highly hippocampus-dependent behaviour, might reveal behavioural correlates of hippocampal dysfunction in non-demented ALS patients. METHODS: We conducted a prospective study of spatial cognition in 43 non-demented ALS outpatients (11f, 32 m, mean age 60.0 years, mean disease duration 27.0 months, mean ALSFRS-R score 40.0) and 43 healthy controls (14f, 29 m, mean age 57.0 years). Participants were tested with a virtual memory-guided navigation task derived from animal research ("starmaze") that has previously been used in studies of hippocampal function. Participants were further tested with neuropsychological tests of visuospatial memory (SPART, 10/36 Spatial Recall Test), fluency (5PT, five-point test) and orientation (PTSOT, Perspective Taking/Spatial Orientation Test). RESULTS: Patients successfully learned and navigated the starmaze from memory, both in conditions that forced memory of landmarks (success: patients 50.7%, controls 47.7%, p = 0.786) and memory of path sequences (success: patients 96.5%, controls 94.0%, p = 0.937). Measures of navigational efficacy (latency, path error and navigational uncertainty) did not differ between groups (p ≥ 0.546). Likewise, SPART, 5PT and PTSOT scores did not differ between groups (p ≥ 0.238). CONCLUSIONS: This study found no behavioural correlate for hippocampal dysfunction in non-demented ALS patients. These findings support the view that the individual cognitive phenotype of ALS may relate to distinct disease subtypes rather than being a variable expression of the same underlying condition.

Multisensory input modulates memory-guided spatial navigation in humans.

Efficient navigation is supported by a cognitive map of space. The hippocampus plays a key role for this map by linking multimodal sensory information with spatial memory representations. However, in human navigation studies, the full range of sensory information is often unavailable due to the stationarity of experimental setups. We investigated the contribution of multisensory information to memory-guided spatial navigation by presenting a virtual version of the Morris water maze on a screen and in an immersive mobile virtual reality setup. Patients with hippocampal lesions and matched controls navigated to memorized object locations in relation to surrounding landmarks. Our results show that availability of multisensory input improves memory-guided spatial navigation in both groups. It has distinct effects on navigational behaviour, with greater improvement in spatial memory performance in patients. We conclude that congruent multisensory information shifts computations to extrahippocampal areas that support spatial navigation and compensates for spatial navigation deficits.

Confounders for prognostic accuracy of neuron-specific enolase after cardiac arrest: A retrospective cohort study.

AIM: To evaluate neuron-specific enolase (NSE) thresholds for prediction of neurological outcome after cardiac arrest and to analyze the influence of hemolysis and confounders. METHODS: Retrospective analysis from a cardiac arrest registry. Determination of NSE serum concentration and hemolysis-index (h-index) 48-96 hours after cardiac arrest. Evaluation of neurological outcome using the Cerebral Performance Category score (CPC) at hospital discharge. Separate analyses considering CPC 1-3 and CPC 1-2 as good neurological outcome. Analysis of specificity and sensitivity for poor and good neurological outcome prediction with and without exclusion of hemolytic samples (h-index larger than 50). RESULTS: Among 356 survivors three days after cardiac arrest, hemolysis was detected in 28 samples (7.9%). At a threshold of 60 µg/L, NSE predicted poor neurological outcome (CPC 4-5) in all samples with a specificity of 92% (86-95%) and sensitivity of 73% (66-79%). In non-hemolytic samples, specificity was 94% (89-97%) and sensitivity 70% (62-76%). At a threshold of 100 µg/L, specificity was 98% (95-100%, all samples) and 99% (95-100%, non-hemolytic samples), and sensitivity 58% (51-65%) and 55% (47-63%), respectively. Possible confounders for elevated NSE in patients with good neurological outcome were ECMO, malignancies, blood transfusions and acute brain diseases. Nine patients with NSE below 17 µg/L had CPC 5, all had plausible death causes other than hypoxic-ischemic encephalopathy. CONCLUSIONS: NSE concentrations higher than 100 µg/L predicted poor neurological outcome with high specificity. An NSE less than 17 µg/L indicated absence of severe hypoxic-ischemic encephalopathy. Hemolysis and other confounders need to be considered. INSTITUTIONAL PROTOCOL NUMBER: The local ethics committee (board name: Ethikkommission der Charité) approved this study by the number: EA2/066/23, approval date: 28th June 2023, study title "'ROSC' - Resuscitation Outcome Study."

Cortical somatosensory evoked potential amplitudes and clinical outcome after cardiac arrest: a retrospective multicenter study.

OBJECTIVE: Bilaterally absent cortical somatosensory evoked potentials (SSEPs) reliably predict poor outcome in comatose cardiac arrest (CA) patients. Cortical SSEP amplitudes are a recent prognostic extension; however, amplitude thresholds, inter-recording, and inter-rater agreement remain uncertain. METHODS: In a retrospective multicenter cohort study, we determined cortical SSEP amplitudes of comatose CA patients using a standardized evaluation pathway. We studied inter-recording agreement in repeated SSEPs and inter-rater agreement by four raters independently determining 100 cortical SSEP amplitudes. Primary outcome was assessed using the cerebral performance category (CPC) upon intensive care unit discharge dichotomized into good (CPC 1-3) and poor outcome (CPC 4-5). RESULTS: Of 706 patients with SSEPs with median 3 days after CA, 277 (39.2%) had good and 429 (60.8%) poor outcome. Of patients with bilaterally absent cortical SSEPs, one (0.8%) survived with CPC 3 and 130 (99.2%) had poor outcome. Otherwise, the lowest cortical SSEP amplitude in good outcome patients was 0.5 µV. 184 (42.9%) of 429 poor outcome patients had lower cortical SSEP amplitudes. In 106 repeated SSEPs, there were 6 (5.7%) with prognostication-relevant changes in SSEP categories. Following a standardized evaluation pathway, inter-rater agreement was almost perfect with a Fleiss' kappa of 0.88. INTERPRETATION: Bilaterally absent and cortical SSEP amplitudes below 0.5 µV predicted poor outcome with high specificity. A standardized evaluation pathway provided high inter-rater and inter-recording agreement. Regain of consciousness in patients with bilaterally absent cortical SSEPs rarely occurs. High-amplitude cortical SSEP amplitudes likely indicate the absence of severe brain injury.

Cognitive deficits following anti-NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is a recently characterised autoimmune disorder mainly affecting young women. Although the clinical features of the acute disease are well characterised, cognitive long-term outcome has not been examined in detail. METHODS: The authors investigated cognitive performance in nine patients with proven anti-NMDAR encephalitis after recovery from the acute disease period (median 43 months after disease onset, range 23 to 69). Patients underwent a comprehensive neuropsychological assessment, including memory tasks that have previously been shown to be sensitive for hippocampal dysfunction. RESULTS: Substantial persistent cognitive impairments were observed in eight out of nine patients that mainly consisted of deficits in executive functions and memory. The severity of these deficits varied inter-individually. Patients with early immunotherapy performed significantly better. The most severe deficits were observed with inefficient or delayed initial treatment. CONCLUSION: Our results suggest that cognitive deficits constitute a major long-term morbidity of anti-NMDAR encephalitis. These deficits relate to the distribution of NMDARs in the human brain and their functional role in normal cognition. Good cognitive long-term outcome may depend on early and aggressive treatment.