Role of Imaging Modalities and N-Acetylcysteine Treatment in Sepsis-Associated Encephalopathy.

Sepsis-associated encephalopathy is a severe systemic infection complication. Although early stages involve pathophysiological changes, detection using conventional imaging is challenging. Glutamate chemical exchange saturation transfer and diffusion kurtosis imaging can noninvasively investigate cellular and molecular events in early disease stages using magnetic resonance imaging (MRI). N-Acetylcysteine, an antioxidant and precursor of glutathione, regulates neurotransmitter glutamate metabolism and participates in neuroinflammation. We investigated the protective role of n-acetylcysteine in sepsis-associated encephalopathy using a rat model and monitored changes in brain using magnetic resonance (MR) molecular imaging. Bacterial lipopolysaccharide was injected intraperitoneally to induce a sepsis-associated encephalopathy model. Behavioral performance was assessed using the open-field test. Tumor necrosis factor α and glutathione levels were detected biochemically. Imaging was performed using a 7.0-T MRI scanner. Protein expression, cellular damage, and changes in blood-brain barrier permeability were assessed using western blotting, pathological staining, and Evans blue staining, respectively. Lipopolysaccharide-induced rats showed reduced anxiety and depression after treatment with n-acetylcysteine. MR molecular imaging can identify pathological processes at different disease stages. Furthermore, rats treated with n-acetylcysteine showed increased glutathione levels and decreased tumor necrosis factor α, suggesting enhanced antioxidant capacity and inhibition of inflammatory processes, respectively. Western blot analysis showed reduced expression of nuclear factor kappa B (p50) protein after treatment, suggesting that n-acetylcysteine inhibits inflammation via this signaling pathway. Finally, n-acetylcysteine-treated rats showed reduced cellular damage by pathology and reduced extravasation of their blood-brain barrier by Evans Blue staining. Thus, n-acetylcysteine might be a therapeutic option for sepsis-associated encephalopathy and other neuroinflammatory diseases. Furthermore, noninvasive "dynamic visual monitoring" of physiological and pathological changes related to sepsis-associated encephalopathy was achieved using MR molecular imaging for the first time, providing a more sensitive imaging basis for early diagnosis, identification, and prognosis.

Cerebral Blood Flow Alterations in Sepsis-Associated Encephalopathy: A Prospective Observational Study.

BACKGROUND: The timely recognition of sepsis-associated encephalopathy (SAE) remains a challenge. This study aimed to observe the CBF changes via TCD during sepsis and explore their possible predictive value in SAE. METHODS: In this prospective observational study, septic patients were enrolled and classified according to the diagnosis of SAE into two groups: SAE group and non-SAE group. Then SAE patients were further divided into subgroup A (the type with agitation) and subgroup B (the type with depressed consciousness) based on their clinical manifestations. The clinical profiles and TCD parameters within 24 hours of onset were compared between groups and subgroups. RESULTS: Exactly 198 septic patients were enrolled including 65 patients in SAE group (36 male/29 female with a median age of 70) and 133 patients in non-SAE group (75 male/58 female with a median age of 67). Significant elevated peak-systolic velocity (VS; 107 [69-138] cm/s vs 85 [69-101] cm/s, P = .002) of the left middle cerebral artery (MCA) and pulsatility index (PI; left: 0.99 [0.81-1.34] vs 0.89 [0.76-1.00], P < .001; right: 0.99 [0.77-1.21] vs 0.88 [0.78-1.03], P = .007) of bilateral MCAs were found in SAE group compared with non-SAE group. In subgroup analysis, subgroup A (the type with agitation) showed significantly increased VS/VM/VD and lower PI/RI of bilateral MCAs compared with subgroup B (the type with depressed consciousness). The cerebral blood flow volume of subgroup A were obviously higher than subgroup B [858.7 (729.1,876.9) mL/s vs 380.9 (373.3,447.4) mL/s, P < .001]. CONCLUSIONS: This study confirmed the abnormal CBF among SAE and found different types of CBF alterations were related to different clinical features. VS and PI might help clinicians to early identify different types of SAE.

Texture Feature-Based Machine Learning Classification on MRI Image for Sepsis-Associated Encephalopathy Detection: A Pilot Study.

Objective: The objective of this study was to assess the performance of combining MRI-based texture analysis with machine learning for differentiating sepsis-associated encephalopathy (SAE) from sepsis alone. Method: Sixty-six MRI-T1WI images of an SAE patient and 125 images of patients with sepsis alone were collected. Frontal lobe, brain stem, hippocampus, and amygdala were selected as regions of interest (ROIs). 279 texture features of each ROI were obtained using MaZda software. After the dimension reduction, 30 highly discriminative features of each ROI were adopted to differentiate SAE from sepsis alone using the CatBoost model. Results: The classification models of frontal, brain stem, hippocampus, and amygdala were constructed. The classification accuracy was above 0.83, and the area under the curve (AUC) exceeded 0.90 in the validation set. Conclusion: The texture features differed between SAE patients and patients with sepsis alone in different anatomical locations, suggesting that MRI-based texture analysis with machine learning might be helpful in differentiating SAE from sepsis alone.

Elevated sTREM2 and NFL levels in patients with sepsis associated encephalopathy.

PURPOSE: Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis that may lead to cognitive decline. Our aim was to investigate whether the neurofilament light chain (NFL) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) could be utilized as prognostic biomarkers in SAE. MATERIALS AND METHODS: In this prospective observational study, baseline serum levels of sTREM2 and cerebrospinal fluid (CSF) levels of sTREM2 and NFL were measured by ELISA in 11 SAE patients and controls. Patients underwent daily neurological examination. Brain magnetic resonance imaging (MRI) and standard electroencephalography (EEG) were performed. Cognitive dysfunction was longitudinally assessed after discharge in 4 SAE patients using the Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination-Revised (ACE-R) tests. RESULTS: SAE patients showed higher CSF sTREM2 and NFL levels than controls. sTREM2 and NFL levels were not correlated with the severity measures of sepsis. Three months after discharge, 2 SAE patients displayed ACE-R scores congruent with mild cognitive impairment (MCI), persisting in one patient 12 months after discharge. SAE patients with MCI showed higher CSF NFL levels, bacteremia, and abnormal brain MRI. Patients with increased serum/CSF sTREM2 levels showed trends towards displaying poorer attention/orientation and visuo-spatial skills. CONCLUSIONS: sTREM2 and NFL levels may serve as a prognostic biomarker for cognitive decline in SAE. These results lend further support for the involvement of glial activation and neuroaxonal degeneration in the physiopathology of SAE.

Diagnostic value of ONSD in sepsis associated encephalopathy of New Zealand rabbits.

OBJECTIVE: The purpose of the present study was to assess whether optic nerve sheath diameter (ONSD) measured by ultrasound could predict brain injury in sepsis associated encephalopathy (SAE). METHODS: A total of 48 male New Zealand White rabbits were used to establish sepsis model. The levels of neuro-specific enolase (NSE), S100B, myeloperoxidase (MPO), and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immuno sorbent assay and ONSD were measured before modeling, 6 h, 12 h and 24 h after modeling. Sixteen rabbits were sacrificed for hematoxylin-eosin (HE) staining of brain tissue and the brain water content at above time points. Rabbits demonstrated brain injury by HE staining were included in the SAE group, the others were enrolled in the control group. The correlation between ONSD and MPO, NSE and S100B in the SAE group were analyzed. Receiver operator characteristic curves were generated to analyze the area under the curve (AUC), specificity and sensitivity of ONSD values for SAE. RESULTS: Twenty-nine of 48 rabbits had brain injury, while 19 cases were enrolled in the control group. The level of MPO, NSE, S100B, TNF-α at 6 h, 12 h and 24 h in SAE group were all higher than those of the control group with statistical significance. The ONSD in SAE group increased with time and significantly wider than those in the control group. Correlation analysis revealed that ONSD was positively correlated with MPO, NSE and S100B in the SAE group. The AUCs for the ONSD value in diagnosing SAE at 6 h, 12 h and 24 h were 0.864, 0.957, 0.877, respectively. CONCLUSIONS: Alterations in ONSD strongly correlated with MPO, NSE and S100B among SAE rabbits. Monitoring of ONSD exhibited a high predictive value for SAE.

Sepsis-associated encephalopathy and septic encephalitis: an update.

INTRODUCTION: Sepsis-associated encephalopathy (SAE) and septic encephalitis (SE) are associated with increased mortality, long-term cognitive impairment, and focal neurological deficits. AREAS COVERED: The PUBMED database was searched 2016-2020. The clinical manifestation of SAE is delirium, SE additionally is characterized by focal neurological symptoms. SAE is caused by inflammation with endothelial/microglial activation, increase of permeability of the blood-brain-barrier, hypoxia, imbalance of neurotransmitters, glial activation, axonal, and neuronal loss. Septic-embolic (SEE) and septic-metastatic encephalitis (SME) are characterized by focal ischemia (SEE) and small abscesses (SME). The continuum between SAE, SME, and SEE is documented by imaging techniques and autopsies. The backbone of treatment is rapid optimum antibiotic therapy. Experimental approaches focus on modulation of inflammation, stabilization of the blood-brain barrier, and restoration of membrane/mitochondrial function. EXPERT OPINION: The most promising diagnostic approaches are new imaging techniques. The most important measure to fight delirium remains establishment of daily structure and adequate sensory stimuli. Dexmedetomidine and melatonin appear to reduce the frequency of delirium, their efficacy in SAE and SE remains to be established. Drugs already licensed for other indications or available as food supplements which may be effective in SAE are statins, L-DOPA/benserazide, ß-hydroxybutyrate, palmitoylethanolamide, and tetracyclines or other bactericidal non-lytic antibiotics.

Brain Volume Changes in Patients with Acute Brain Dysfunction Due to Sepsis.

BACKGROUND: Sepsis-induced brain dysfunction (SIBD) is often encountered in sepsis patients and is related to increased morbidity. No specific tests are available for SIBD, and neuroimaging findings are often normal. In this study, our aim was to analyze the diagnostic value of volumetric analysis of the brain structures and to find out its significance as a prognostic measure. METHODS: In this prospective observational study, brain magnetic resonance imaging (MRI) sections of 25 consecutively enrolled SIBD patients (17 with encephalopathy and 8 with coma) and 22 healthy controls underwent volumetric evaluation by an automated segmentation method. RESULTS: Ten SIBD patients had normal MRI, and 15 patients showed brain lesions or atrophy. The most prominent volume reduction was found in cerebral and cerebellar white matter, cerebral cortex, hippocampus, and amygdala, whereas deep gray matter regions and cerebellar cortex were relatively less affected. SIBD patients with normal MRI showed significantly reduced volumes in hippocampus and cerebral white matter. Caudate nuclei, putamen, and thalamus showed lower volume values in non-survivor SIBD patients, and left putamen and right thalamus showed a more pronounced volume reduction in coma patients. CONCLUSIONS: Volumetric analysis of the brain appears to be a sensitive measure of volumetric changes in SIBD. Volume reduction in specific deep gray matter regions might be an indicator of unfavorable outcome.

[The clinical significance of transcranial Doppler in early diagnosis of sepsis-associated encephalopathy].

Objective: To investigate the clinical significance of transcranial Doppler (TCD) in early diagnosis of sepsis-associated encephalopathy(SAE). Methods: Septic patients admitted to the intensive care unit(ICU) were recruited at Xiangya Hospital, Central South University from July 2015 to March 2016. Clinical data and TCD parameters during 24 hours after admission were collected. All patients were screened for delirium using the confusion assessment method for the intensive care unit (CAM-ICU) twice a day. The gold standard of the diagnosis of SAE was positive CAM-ICU evaluation. Patients were divided into SAE group and the non-SAE group. TCD data including systolic velocity (Vs), diastolic velocity (Vd), mean velocity (Vm), pulsatility index (PI) and resistant index (RI) were analyzed to determine the optimal diagnostic cut-off value. Results: A total of 43 patients were enrolled including 12 in SAE group and 31 in non-SAE group. Vm and Vd were lower in SAE group [Vm: (53.50±12.22) cm/s vs. (61.68±9.63) cm/s, P<0.05; Vd: (33.42±10.87) cm/s vs. (43.16±7.84) cm/s, P<0.01] but PI and RI were significant higher in SAE group[PI:(1.16±0.2) vs. (0.90±0.15), P<0.01;RI:(0.65±0.08) vs. (0.56±0.06), P<0.01] than in non-SAE group. The cut-off values of Vs, Vm, Vd, PI and RI for the diagnosis of SAE were 112cm/s, 55.50cm/s, 34.50cm/s, 1.16, 0.65, respectively, with the relevant sensitivities of 19.4%, 83.9%, 93.5%, 58.3%, 58.3% and the specificities of 100.0%, 50.0%, 58.3%, 96.8%, 96.8%, respectively. The diagnostic AUC of Vd, PI and RI were 0.741, 0.808 and 0.808 respectively. Conclusions: The parameter changes of TCD suggest that the pathogenesis of SAE is related to cerebral hypoperfusion, TCD is a helpful method for the early diagnosis of SAE.

Altered intrinsic activity and functional connectivity in two animal models with opposing fear memories.

Post-traumatic stress disorder and sepsis-associated encephalopathy are two common neuropsychiatric disorders, but to some extent with opposing cognitive performance. However, the neural mechanisms underlying these two different phenomena remain poorly understood. In our study, the amplitude of low-frequency fluctuations (ALFF) of spontaneous blood oxygen level-dependent signals was used to assess regional disturbances in two animal models with opposing cognitive performance, namely post-traumatic stress disorder and sepsis-associated encephalopathy. Then, we examined whether the memory-relevant brain regions with impaired ALFF altered functional connectivity within the whole brain. Here, we showed that lipopolysaccharide challenge and footshock induced significantly different cognitive performance. We found significant group differences in ALFF in the bilateral dentate gyrus. In addition, our study showed that footshocks induced a significant decrease in functional connectivity between the left dentate gyrus and the visual cortex compared with the lipopolysaccharide group. Notably, cognitive performance was associated with ALFF values in the right dentate gyrus. In conclusion, our data suggested that damaged regional spontaneous activity and abnormal functional connectivity might be differently involved in two opposing fear memories.

Assessing long-term neuroinflammatory responses to encephalopathy using MRI approaches in a rat endotoxemia model.

Sepsis-associated encephalopathy (SAE) induces neuroinflammation, which is associated with cognitive impairment (CI). CI is also correlated with aging. We used contrast-enhanced magnetic resonance imaging (MRI), perfusion MRI, and MR spectroscopy to assess long-term alterations in BBB permeability, microvascularity, and metabolism, respectively, in a rat lipopolysaccharide-induced SAE model. Free radical-targeted molecular MRI was used to detect brain radical levels at 24 h and 1 week post-LPS injection. CE-MRI showed increased Gd-DTPA uptake in LPS rat brains at 24 h in cerebral cortex, hippocampus, thalamus, and perirhinal cortex regions. Increased MRI signal intensities were observed in LPS rat brains in cerebral cortex, perirhinal cortex, and hippocampus regions 1 week post-LPS. Long-term BBB dysfunction was detected in the cerebral cortex at 6 weeks post-LPS. Increased relative cerebral blood flow (rCBF) in cortex and thalamus regions at 24 h, decreased cortical and hippocampal rCBF at 6 weeks, decreased cortical rCBF at 3 and 12 weeks, and increased thalamus rCBF at 6 weeks post-LPS, were detected. MRS indicated that LPS-exposed rat brains had decreased: NAA/Cho metabolite ratios at 1, 3, 6, and 12 weeks; Cr/Cho at 1, 3, and 12 weeks; and Myo-Ins/Cho at 1, 3, and 6 weeks post-LPS. Free radical imaging detected increased radical levels in LPS rat brains at 24 h and 1 week post-LPS. LPS-exposed rats were compared to saline-treated controls. We clearly demonstrated BBB dysfunction, impaired vascularity, and decreased brain metabolites, as measures of long-term neuroinflammatory indicators, as well as increased free radicals in a LPS-induced rat SAE model.

Transcranial Doppler to assess sepsis-associated encephalopathy in critically ill patients.

BACKGROUND: Transcranial Doppler can detect cerebral perfusion alteration in septic patients. We correlate static Transcranial Doppler findings with clinical signs of sepsis-associated encephalopathy. METHODS: Forty septic patients were examined with Transcranial Doppler on the first and third day of sepsis diagnosis. The pulsatility index (PI) and cerebral blood flow index (CBFi) were calculated by blood velocity in the middle cerebral artery (cm/sec). Patients underwent a daily cognitive assessment with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) test. RESULTS: Twenty-one patients (55%) were found to present confusion. The majority of the patients presented a PI > 1.1 (76%). PI on the first day (but not the third day) could predict a positive CAM-ICU test in septic patients (PI cut-off: 1.3, AUC: 0.905, p < 0.01, sensitivity: 95%, specificity: 88%, AUC: 0.618, p = 0.24). Multivariable analysis showed that PI on the first day is related to a positive CAM-ICU test independent of age and APACHE II score (OR: 5.6, 95% CI: 1.1-29, p = 0.03). A decrease of the PI on the third day was observed in the group that presented initially high PI (>1.3) (2.2 ± 0.71 vs. 1.81 ± 0.64; p = 0.02). On the other hand, an increase in PI was observed in the other patients (1.01 ± 0.15 vs. 1.58 ± 0.57; p < 0.01). On only the first day, the mean blood velocity in the middle cerebral artery and CBFi were found to be lower in those patients with a high initial PI (36 ± 21 vs. 62 ± 28 cm/sec; p < 0.01, 328 ± 101 vs. 581 ± 108; p < 0.01, respectively). CONCLUSIONS: Cerebral perfusion disturbance observed with Transcranial Doppler could explain clinical symptoms of sepsis-associated encephalopathy.

Impaired cerebrovascular autoregulation in patients with severe sepsis and sepsis-associated delirium.

INTRODUCTION: Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis. METHODS: Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2. RESULTS: 30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035). CONCLUSIONS: AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD. TRIAL REGISTRATION: clinicalTrials.gov ID NCT01029080.