The Impact of Burst Motor Cortex Stimulation on Cardiovascular Autonomic Modulation in Chronic Pain: A Feasibility Study for a New Approach to Objectively Monitor Therapeutic Effects.

INTRODUCTION: Chronic refractory pain of various origin occurs in 30-45% of pain patients, and a considerable proportion remains resistant to pharmacological and behavioral therapies, requiring adjunctive neurostimulation therapies. Chronic pain is known to stimulate sympathetic outflow, yet the impact of burst motor cortex stimulation (burstMCS) on objectifiable autonomic cardiovascular parameters in chronic pain remains largely unknown. METHODS: In three patients with chronic pain (2 facial pain/1 post-stroke pain), we compared pain intensity using a visual analog scale (VAS 1-10) and parameters of autonomic cardiovascular modulation at supine rest, during parasympathetic challenge with six cycles per minute of metronomic deep breathing, and during sympathetic challenge (active standing) at baseline and after 4 months of burstMCS compared to age-/gender-matched healthy controls. RESULTS: While two out of three patients were responsive after 4 months of adjunctive burstMCS (defined as pain reduction of > 30%), no differences were found in any of the three patients regarding the R-R intervals of adjacent QRS complexes (RRI, 642 vs. 676 ms) and blood pressure (BP, 139/88 vs. 141/90 mmHg). Under resting conditions, parameters of parasympathetic tone [normalized units of high-frequency oscillations of RRI (RRI-HFnu power) 0.24 vs. 0.38, root-mean-square differences of successive RRI (RRI-RMSSD) 7.7 vs. 14.7 ms], total autonomic cardiac modulation [RRI total power 129.3 vs. 406.2 ms2, standard deviation of RRI (RRI-SD) 11.6 vs. 18.5 ms, coefficient of variation of RRI (RRI-CV) 1.9 vs. 3.7%], and baroreceptor reflex sensitivity (BRS, 1.9 vs. 2.3 ms/mmHg) increased, and parameters of sympathetic tone [normalized units of low-frequency oscillations of RRI (RRI-LFnu power) 0.76 vs. 0.62] and sympatho-vagal balance [ratio of RR-LF to RRI-HF power (RRI-LF/HF ratio) 3.4 vs. 1.9] decreased after 4 months of burstMCS. Low-frequency oscillations of systolic blood pressure (SBP-LF power), a parameter of sympathetic cardiovascular modulation, increased slightly (17.6 vs. 20.4 mmHg2). During parasympathetic stimulation, the expiratory-inspiratory ratio (E/I ratio) increased slightly, while upon sympathetic stimulation, the ratio between the shortest RRI around the 15th heartbeat and the longest RRI around the 30th heartbeat after standing up (RRI 30/15 ratio) remained unchanged. CONCLUSION: Four months of adjunctive burstMCS was associated with an increase in parameters reflecting both total and parasympathetic autonomic modulation and baroreceptor reflex sensitivity. In contrast, sympathetic tone declined in our three patients, suggesting stimulation-associated improvement not only in subjectively perceived VAS pain scores, but also in objectifiable parameters of autonomic cardiovascular modulation.

Pupillometry in the follow-up of patients undergoing EVT - prediction of space-occupying hemispheric infarction.

BACKGROUND: Despite benefits of endovascular treatment (EVT) for large vessel occlusion (LVO) ischemic stroke, space-occupying brain edema (BE) represents a detrimental complication. In critical-care settings, CT-imaging is needed for monitoring these patients. Yet, bed-side techniques with the potential to predict whether patients develop BE or not would facilitate a time- and cost-efficient patient care. We assessed clinical significance of automated pupillometry in the follow-up of patients undergoing EVT. METHODS: From 10/2018 to 10/2021, neurocritical-care-unit patients were retrospectively enrolled after EVT of anterior circulation LVO. We monitored parameters of pupillary reactivity [light-reflex-latency (Lat), constriction- and redilation-velocities (CV, DV), percentage-change-of-apertures (per-change); NeurOptics-pupilometer®] up to every hour on day 1-3 of ICU stay. BE was defined as midline shift ≥ 5 mm on follow-up imaging 3-5 days after EVT. We calculated mean values of intra-individual differences between successive pairs of parameters (mean-deltas), determined best discriminative cut-off values for BE development (ROC-analyses), and evaluated prognostic performance of pupillometry for BE development (sensitivity/specificity/positive-/negative-predictive-values). RESULTS: 3241 pupillary assessments of 122 patients [67 women, 73 years (61.0-85.0)] were included. 13/122 patients developed BE. Patients with BE had significantly lower CVs, DVs, and smaller per-changes than patients without BE. On day 1 after EVT mean-deltas of CV, DV, and per-changes were significantly lower in patients with than without BE. Positive-predictive-values of calculated thresholds to discriminate both groups were considerably low, yet, we found high negative-predictive-values for CV, DV, per-changes, and mean-deltas (max.: 98.4%). CONCLUSION: Our data suggest associations between noninvasively detected changes in pupillary reactivity and BE early after LVO-EVT. Pupillometry may identify patients who are unlikely to develop BE and may not need repetitive follow-up-imaging or rescue-therapy.

Prognostic Accuracy of CTP Summary Maps in Patients with Large Vessel Occlusive Stroke and Poor Revascularization after Mechanical Thrombectomy-Comparison of Three Automated Perfusion Software Applications.

Background: Innovative automated perfusion software solutions offer support in the management of acute stroke by providing information about the infarct core and penumbra. While the performance of different software solutions has mainly been investigated in patients with successful recanalization, the prognostic accuracy of the hypoperfusion maps in cases of futile recanalization has hardly been validated. Methods: In 39 patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation and poor revascularization (thrombolysis in cerebral infarction (TICI) 0-2a) after mechanical thrombectomy (MT), hypoperfusion analysis was performed using three different automated perfusion software solutions (A: RAPID, B: Brainomix e-CTP, C: Syngo.via). The hypoperfusion volumes (HV) as Tmax > 6 s were compared with the final infarct volumes (FIV) on follow-up CT 36−48 h after futile recanalization. Bland−Altman analysis was applied to display the levels of agreement and to evaluate systematic differences. Based on the median hypoperfusion intensity ratio (HIR, volumetric ratio of tissue with a Tmax > 10 s and Tmax > 6 s) patients were dichotomized into high- and low-HIR groups. Subgroup analysis with favorable (<0.6) and unfavorable (≥0.6) HIR was performed with respect to the FIV. HIR was correlated to clinical baseline and outcome parameters using Pearson's correlation. Results: Overall, there was good correlation without significant differences between the HVs and the FIVs with package A (r = 0.78, p < 0.001) being slightly superior to B and C. However, levels of agreement were very wide for all software applications in Bland-Altman analysis. In cases of large infarcts exceeding 150 mL the performance of the automated software solutions generally decreased. Subgroup analysis revealed the FIV to be generally underestimated in patients with HIR ≥ 0.6 (p < 0.05). In the subgroup with favorable HIR, however, there was a trend towards an overestimation of the FIV. Nevertheless, packages A and B showed good correlation between the HVs and FIVs without significant differences (p > 0.2), while only package C significantly overestimated the FIV (−54.6 ± 56.0 mL, p = 0.001). The rate of modified Rankin Scale (mRS) 0−3 after 3 months was significantly higher in favorable vs. unfavorable HIR (42.1% vs. 13.3%, p = 0.02). Lower HIR was associated with higher Alberta Stroke Program Early CT Score (ASPECTS) at presentation and on follow-up imaging, lower risk of malignant edema, and better outcome (p < 0.05). Conclusion: Overall, the performance of the automated perfusion software solutions to predict the FIV after futile recanalization is good, with decreasing accuracy in large infarcts exceeding 150 mL. However, depending on the HIR, FIV can be significantly over- and underestimated, with Syngo showing the widest range. Our results indicate that the HIR can serve as valuable parameter for outcome predictions and facilitate the decision whether or not to perform MT in delicate cases.

Correlation between clinical severity and extent of autonomic cardiovascular impairment in the acute phase of subarachnoid hemorrhage.

BACKGROUND AND AIM: To assess associations between clinical severity and possible dysfunction of autonomic cardiovascular modulation within the acute phase after spontaneous subarachnoid hemorrhage (SAH). METHODS: In this prospective observational study, in 51 patients with spontaneous SAH, Hunt-and-Hess scores (H&H) were assessed and cardiovascular autonomic modulation was monitored within 24 h after SAH-onset. From 5 min time-series of R-R-intervals (RRI) and blood-pressure (BP) recordings, we calculated autonomic parameters including time-domain [RRI-coefficient-of-variation (RRI-CV) and square-root-of-the-mean-squared-differences-of-successive-RRIs (RMSSD)] and frequency-domain parameters [low- and high-frequency-powers of RRI- and BP-modulation (RRI-LF-, RRI-HF-, SBP-LF-powers) and RRI-total-powers]. Data were compared to those of 20 healthy volunteers. RESULTS: RRI- and BP-values did not differ between groups. Yet, parameters of sympathetic (RRI-LF-powers 141.0 (18.9-402.4) ms2 vs 442.3 (246.8-921.2) ms2, p = 0.001) and total autonomic modulation (RRI-CV 2.4 (1.2-3.7) ms2 vs 3.7 (3.1-5.3) ms2, p = 0.001) were significantly lower in patients than in controls. Subgroup analyses (patients with H&H < 3 vs H&H ≥ 3) and Spearman-rank-correlations revealed increasing loss of sympathetic (RRI-LF-powers 338.6 (179.7-710.4) ms2 vs 72.1 (10.1-175.9) ms2, p = 0.001, rho = - 0.524) and total autonomic modulation (RRI-CV 3.5 (2.3-5.4) ms2 vs 1.6 (1.0-2.8) ms2, p < 0.001, rho = - 0.519) with higher H&H-scores. Multiple-logistic-regression underlined the significant influence of H&H-scores on sympathetic (RRI-LF-powers, p = 0.033) and total autonomic modulation (RRI-CV, p = 0.040) compared to possible confounders (e.g., age, intubation). CONCLUSION: Within the acute phase, spontaneous SAH induces a decrease in sympathetic and total autonomic cardiovascular modulation. Higher H&H-scores were associated with increasing autonomic dysfunction and may therefore augment the risk of cardiovascular complications and poor clinical outcome.

Simplified Edinburgh CT Criteria for Identification of Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: In patients with lobar intracerebral hemorrhage (ICH), etiologic characterization represents a tradeoff between feasibility, resource allocation, and diagnostic certainty. This study investigated the accuracy and clinical utility of the simplified Edinburgh CT criteria to identify underlying cerebral amyloid angiopathy (CAA). METHODS: This external validation analyzed 210 consecutive patients with lobar ICH and available CT and MRI studies from a prospective single-center observational cohort study (2006-2015, Longitudinal Cohort Study on ICH Care [UKER-ICH,] NCT03183167). We investigated the interrater variability and diagnostic accuracy of the simplified Edinburgh CT-based criteria for identification of ICH associated with probable CAA according to MRI-based modified Boston criteria as a reference standard. We evaluated the utility of the simplified Edinburgh criteria by decision curve analysis, comparing the theoretical clinical net benefit (weighted benefit-harm at varying threshold probabilities) of the high-risk category (finger-like projections and subarachnoid hemorrhage) for ruling in and the low-risk category (neither finger-like projections nor subarachnoid hemorrhage) for ruling out with the assumptions of no or all patients having CAA (default strategies). RESULTS: Of 210 patients, 70 (33.3%) had high risk, 67 (31.9%) had medium risk, and 73 (34.8%) had low risk for CAA-associated ICH according to simplified Edinburgh CT criteria, showing moderate interrater variability. Discrimination was good (area under the receiver operating characteristics curve 0.74, 95% CI 0.67-0.81) without evidence of poor calibration (Hosmer-Lemeshow, p = 0.54) for validation of MRI-based diagnosis of probable CAA (n = 94 of 210, 44.8%). The rule-in criteria (high risk), had 87.1% (79.3%-92.3%) specificity, and the rule-out criteria (low risk), had 80.9% (71.1%-88.0%) sensitivity. Decision curve analysis suggested a theoretical clinical net benefit for ruling in but not for ruling out probable CAA compared to default strategies. DISCUSSION: Applying the simplified Edinburgh CT criteria during diagnostic workup seems clinically useful and may accurately identify CAA in patients with lobar ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03183167. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with lobar hemorrhages, the simplified Edinburgh criteria accurately identify those at high risk of CAA.

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage.

BACKGROUND: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far. OBJECTIVE: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors. METHODS: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months. RESULTS: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health. CONCLUSION: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.

Automated Pupillometry Identifies Absence of Intracranial Pressure Elevation in Intracerebral Hemorrhage Patients.

INTRODUCTION: Although automated pupillometry is increasingly used in critical care settings, predictive value of automatically assessed pupillary parameters during different intracranial pressure (ICP) levels and possible clinical implications are unestablished. METHODS: This retrospective cohort study at the neurocritical care unit of the University of Erlangen-Nuremberg (2016-2018) included 23 nontraumatic supratentorial (intracerebral hemorrhage) ICH patients without signs of abnormal pupillary function by manual assessment, i.e., absent light reflex. We assessed ICP levels by an external ventricular drain simultaneously with parameters of pupillary reactivity [i.e., maximum and minimum apertures, light reflex latency (Lat), constriction and redilation velocities (CV, DV), and percentage change of apertures (per-change)] using a portable pupillometer (NeurOptics®). Computed tomography (CT) scans were analyzed to determine lesion location, size, intraventricular hemorrhage, hydrocephalus, midline shift, and compression or absence of the basal cisterns. We performed receiver operating characteristics analysis to investigate associations of ICP levels with pupillary parameters and to determine best cutoff values for prediction of ICP elevation. After dichotomization of assessments according to ICP values (normal: < 20 mmHg, elevated: ≥ 20 mmHg), prognostic performance of the determined cutoff parameters of pupillary function versus of CT-imaging findings was analyzed by calculating sensitivity, specificity, positive and negative predictive values (logistic regression, corresponding ORs with 95% CIs). RESULTS: In 23 patients (11 women, median age 59.0 (51.0-69.0) years), 1,934 assessments were available for analysis. A total of 74 ICP elevations ≥ 20 mmHg occurred in seven patients. Best discriminative thresholds for ICP elevation were: CV < 0.8 mm/s (AUC 0.740), per-change < 10% (AUC 0.743), DV < 0.2 mm/s (AUC 0.703), and Lat > 0.3 s (AUC 0.616). Positive predictive value of all four parameters to indicate ICP elevation ranged between 7.2 and 8.3% only and was similarly low for CT abnormalities (9.1%). We found high negative predictive values of pupillary parameters [CV: 99.2% (95% CI 98.3-99.6), per-change: 98.7% (95% CI 97.8-99.2), DV: 98.0% (95% CI 97.0-98.7), Lat: 97.0% (95% CI 96.0-97.7)], and CT abnormalities [99.7% (95% CI 99.2-99.9)], providing evidence that both techniques adequately identified ICH patients without ICP elevation. CONCLUSIONS: Our data suggest an association between noninvasively detected changes in pupillary reactivity and ICP levels in sedated ICH patients. Although automated pupillometry and neuroimaging seem not sufficient to noninvasively indicate ICP elevation, both techniques, however, adequately identified ICH patients without ICP elevation. This finding may facilitate routine management by saving invasive ICP monitoring or repeated CT controls in patients with specific automated pupillometry readings.