Evaluation and treatment approaches for neurological post-acute sequelae of COVID-19: A consensus statement and scoping review from the global COVID-19 neuro research coalition.

Post-acute neurological sequelae of COVID-19 affect millions of people worldwide, yet little data is available to guide treatment strategies for the most common symptoms. We conducted a scoping review of PubMed/Medline from 1/1/2020-4/1/2023 to identify studies addressing diagnosis and treatment of the most common post-acute neurological sequelae of COVID-19 including: cognitive impairment, sleep disorders, headache, dizziness/lightheadedness, fatigue, weakness, numbness/pain, anxiety, depression and post-traumatic stress disorder. Utilizing the available literature and international disease-specific society guidelines, we constructed symptom-based differential diagnoses, evaluation and management paradigms. This pragmatic, evidence-based consensus document may serve as a guide for a holistic approach to post-COVID neurological care and will complement future clinical trials by outlining best practices in the evaluation and treatment of post-acute neurological signs/symptoms.

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.

The Neurological Pupil index for outcome prognostication in people with acute brain injury (ORANGE): a prospective, observational, multicentre cohort study.

BACKGROUND: Improving the prognostication of acute brain injury is a key element of critical care. Standard assessment includes pupillary light reactivity testing with a hand-held light source, but findings are interpreted subjectively; automated pupillometry might be more precise and reproducible. We aimed to assess the association of the Neurological Pupil index (NPi)-a quantitative measure of pupillary reactivity computed by automated pupillometry-with outcomes of patients with severe non-anoxic acute brain injury. METHODS: ORANGE is a multicentre, prospective, observational cohort study at 13 hospitals in eight countries in Europe and North America. Patients admitted to the intensive care unit after traumatic brain injury, aneurysmal subarachnoid haemorrhage, or intracerebral haemorrhage were eligible for the study. Patients underwent automated infrared pupillometry assessment every 4 h during the first 7 days after admission to compute NPi, with values ranging from 0 to 5 (with abnormal NPi being <3). The co-primary outcomes of the study were neurological outcome (assessed with the extended Glasgow Outcome Scale [GOSE]) and mortality at 6 months. We used logistic regression to model the association between NPi and poor neurological outcome (GOSE ≤4) at 6 months and Cox regression to model the relation of NPi with 6-month mortality. This study is registered with ClinicalTrials.gov, NCT04490005. FINDINGS: Between Nov 1, 2020, and May 3, 2022, 514 patients (224 with traumatic brain injury, 139 with aneurysmal subarachnoid haemorrhage, and 151 with intracerebral haemorrhage) were enrolled. The median age of patients was 61 years (IQR 46-71), and the median Glasgow Coma Scale score on admission was 8 (5-11). 40 071 NPi measurements were taken (median 40 per patient [20-50]). The 6-month outcome was assessed in 497 (97%) patients, of whom 160 (32%) patients died, and 241 (47%) patients had at least one recording of abnormal NPi, which was associated with poor neurological outcome (for each 10% increase in the frequency of abnormal NPi, adjusted odds ratio 1·42 [95% CI 1·27-1·64]; p<0·0001) and in-hospital mortality (adjusted hazard ratio 5·58 [95% CI 3·92-7·95]; p<0·0001). INTERPRETATION: NPi has clinically and statistically significant prognostic value for neurological outcome and mortality after acute brain injury. Simple, automatic, repeat automated pupillometry assessment could improve the continuous monitoring of disease progression and the dynamics of outcome prediction at the bedside. FUNDING: NeurOptics.

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.

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.

Cardiovascular medication seems to promote recovery of autonomic dysfunction after stroke.

BACKGROUND: Stroke may compromise cardiovascular-autonomic modulation (CAM). The longitudinal post-stroke CAM alterations remain unclear as previous studies excluded patients with cardiovascular medication. This study evaluated whether CAM dysfunction improves after several months in patients under typical clinical conditions, i.e., without excluding patients with cardiovascular medication. METHODS: In 82 ischemic stroke patients [33 women, 64.9 ± 8.9 years, NIHSS-scores 2 (interquartile range 1-5)], we evaluated the applications of cardiovascular medication before stroke, during autonomic tests performed within 1 week, 3 and 6 months after stroke onset. We determined resting RR intervals (RRI), systolic, diastolic blood pressures (BPsys), respiration, parameters reflecting total CAM [RRI-standard deviation (RRI-SD), RRI-total powers], sympathetic [RRI-low-frequency powers (RRI-LF), BPsys-LF powers] and parasympathetic CAM [RMSSD, RRI-high-frequency powers (RRI-HF powers)], and baroreflex sensitivity. ANOVA or Friedman tests with post hoc analyses compared patient data with data of 30 healthy controls, significance was assumed for P < 0.05. RESULTS: More patients had antihypertensive medication after than before stroke. First-week CAM testing showed lower RRIs, RMSSD, RRI-SDs, RRI-total powers, RRI-HF powers, and baroreflex sensitivity, but higher BPsys-LF powers in patients than controls. After 3 and 6 months, patients had significantly higher RRIs, RRI-SDs, RRI-total powers, RMSSDs, RRI-HF powers, and baroreflex sensitivity, but lower BPsys-LF powers than in the 1st week; RMSSDs and RRI-HF powers no longer differed between patients and controls. However, 6-month values of RRIs, RRI-SDs, and baroreflex sensitivity were again lower in patients than controls. CONCLUSIONS: Even mild strokes compromised cardiovagal modulation and baroreflex sensitivity. After 3 months, CAM had almost completely recovered. Recovery might be related to the mild stroke severity. Presumably, CAM recovery was also promoted by the increased application of cardiovascular medication. Yet, slight CAM dysfunction after 6 months suggests continuing autonomic vulnerability.

Posterior circulation ischemic stroke not involving the brainstem is associated with cardiovascular autonomic dysfunction.

BACKGROUND AND PURPOSE: Ischemic stroke may induce cardiovascular autonomic dysfunction, but most previous studies have included patients with anterior circulation ischemic stroke or brainstem stroke. It remains unclear whether posterior circulation ischemic stroke (PCIS) without brainstem involvement also compromises cardiovascular autonomic modulation (CAM). Therefore, we aimed to assess CAM in PCIS patients with and without brainstem involvement. METHODS: In four subgroups of 61 PCIS patients (14 occipital lobe, 16 thalamic, 12 cerebellar, and 19 brainstem strokes) and 30 healthy controls, we recorded RR intervals (RRIs), systolic (SBP) and diastolic blood pressure (DBP), and respiration at supine rest during the first week after stroke onset. We calculated parameters reflecting total CAM (RRI-standard deviation [RRI-SD], RRI-total powers), predominantly sympathetic CAM (RRI-low-frequency [LF] powers and SBP-LF powers] and parasympathetic CAM (root mean square of successive RRI differences [RMSSD], RRI-high-frequency [HF] powers), sympathetic-parasympathetic balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). Values were compared among the four PCIS groups and controls using one-way ANOVA Kruskal-Wallis tests, with post-hoc analyses. Significance was assumed for p < 0.05. RESULTS: In each PCIS subgroup, values for RRI, RRI-SD, RMSSD, RRI-HF powers, and BRS were significantly lower, while SBP-LF powers were higher than in the controls. Only in patients with occipital lobe stroke were RRI-LF/HF ratios significantly higher than in controls. Otherwise, autonomic variables did not differ among the four PCIS subgroups. CONCLUSIONS: During the first week after stroke onset, our PCIS patients with occipital lobe, thalamic, cerebellar, or brainstem strokes all had reduced cardiovagal modulation, compromised baroreflex, and increased peripheral sympathetic modulation. The RRI-LF/HF ratios suggest that sympathetic predominance is slightly more prominent after occipital lobe stroke. PCIS may trigger cardiovascular autonomic dysfunction even without brainstem involvement.

Acute care and secondary prevention of stroke with newly detected versus known atrial fibrillation.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) in stroke patients can be classified as either "known AF" (KAF), defined as AF confirmed before stroke onset, or "AF detected after stroke" (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype. METHODS: Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention. RESULTS: A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42-16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly. CONCLUSIONS: Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype.

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.

Neutrophil-to-lymphocyte ratio is associated with increased cerebral blood flow velocity in acute bacterial meningitis.

In community-acquired bacterial meningitis (CABM) intracranial vascular alterations are devastating complications which are triggered by neuroinflammation and result in worse clinical outcome. The Neutrophil-to-Lymphocyte ratio (NLR) represents a reliable parameter of the inflammatory response. In this study we analyzed the association between NLR and elevated cerebral blood flow velocity (CBFv) in CABM-patients. This study included all (CABM)-patients admitted to a German tertiary center between 2006 and 2016. Patients' demographics, in-hospital measures, neuroradiological data and clinical outcome were retrieved from institutional databases. CBFv was assessed by transcranial doppler (TCD). Patients', radiological and laboratory characteristics were compared between patients with/without elevated CBFv. Multivariate-analysis investigated parameters independently associated with elevated CBFv. Receiver operating characteristic(ROC-)curve analysis was undertaken to identify the best cut-off for NLR to discriminate between increased CBFv. 108 patients with CABM were identified. 27.8% (30/108) showed elevated CBFv. Patients with elevated CBFv and normal CBFv, respectively had a worse clinical status on admission (Glasgow Coma Scale: 12 [9-14] vs. 14 [11-15]; p = 0.005) and required more often intensive care (30/30 [100.0%] vs. 63/78 [80.8%]; p = 0.01).The causative pathogen was S. pneumoniae in 70%. Patients with elevated CBFv developed more often cerebrovascular complications with delayed cerebral ischemia (DCI) within hospital stay (p = 0.031). A significantly higher admission-NLR was observed in patients with elevated CBFv (median [IQR]: elevated CBFv:24.0 [20.4-30.2] vs. normal CBFv:13.5 [8.4-19.5]; p < 0.001). Multivariate analysis, revealed NLR to be significantly associated with increased CBFv (Odds ratio [95%CI] 1.042 [1.003-1.084]; p = 0.036). ROC-analysis identified a NLR of 20.9 as best cut-off value to discriminate between elevated CBFv (AUC = 0.713, p < 0.0001, Youden's Index = 0.441;elevated CBFv: NLR ≥ 20.9 19/30[63.5%] vs. normal CBFv: NLR > 20.9 15/78[19.2%]; p < 0.001). Intracranial vascular complications are common among CABM-patients and are a risk factor for unfavorable outcome at discharge. Elevated NLR is independently associated with high CBFv and may be useful in predicting patients' prognosis.

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.

Neck cooling induces blood pressure increase and peripheral vasoconstriction in healthy persons.

INTRODUCTION: Noninvasive temperature modulation by localized neck cooling might be desirable in the prehospital phase of acute hypoxic brain injuries. While combined head and neck cooling induces significant discomfort, peripheral vasoconstriction, and blood pressure increase, localized neck cooling more selectively targets blood vessels that supply the brain, spares thermal receptors of the face and skull, and might therefore cause less discomfort cardiovascular side effects compared to head- and neck cooling. The purpose of this study is to assess the effects of noninvasive selective neck cooling on cardiovascular parameters and cerebral blood flow velocity (CBFV). METHODS: Eleven healthy persons (6 women, mean age 42 ± 11 years) underwent 90 min of localized dorsal and frontal neck cooling (EMCOOLS Brain.Pad™) without sedation. Before and after cooling onset, and after every 10 min of cooling, we determined rectal, tympanic, and neck skin temperatures. Before and after cooling onset, after 60- and 90-min cooling, we monitored RR intervals (RRI), systolic, diastolic blood pressures (BPsys, BPdia), laser Doppler skin blood flow (SBF) at the index finger pulp, and CBFV at the proximal middle cerebral artery (MCA). We compared values before and during cooling by analysis of variance for repeated measurements with post hoc analysis (significance: p < 0.05). RESULTS: Neck skin temperature dropped significantly by 9.2 ± 4.5 °C (minimum after 40 min), while tympanic temperature decreased by only 0.8 ± 0.4 °C (minimum after 50 min), and rectal temperature by only 0.2 ± 0.3 °C (minimum after 60 min of cooling). Index finger SBF decreased (by 83.4 ± 126.0 PU), BPsys and BPdia increased (by 11.2 ± 13.1 mmHg and 8.0 ± 10.1 mmHg), and heart rate slowed significantly while MCA-CBFV remained unchanged during cooling. CONCLUSIONS: While localized neck cooling prominently lowered neck skin temperature, it had little effect on tympanic temperature but significantly increased BP which may have detrimental effects in patients with acute brain injuries.

Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury.

OBJECTIVE: After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. METHODS: In 51 post-moderate-severe-TBI patients (32.7 ±â€¯10.5 years old, 43.1 ±â€¯33.4 months post-injury), and 30 controls (29.1 ±â€¯9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). RESULTS: At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. CONCLUSIONS: In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. SIGNIFICANCE: Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI.

Severity of traumatic brain injury correlates with long-term cardiovascular autonomic dysfunction.

After traumatic brain injury (TBI), central autonomic dysfunction might contribute to long-term increased mortality rates. Central autonomic dysfunction might depend on initial trauma severity. This study was performed to evaluate differences in autonomic modulation at rest and upon standing between patients with a history of mild TBI (post-mild-TBI patients), moderate or severe TBI (post-moderate-severe-TBI patients), and healthy controls. In 20 post-mild-TBI patients (6-78 months after TBI), age-matched 20 post-moderate-severe-TBI patients (6-94 months after TBI) and 20 controls, we monitored respiration, RR intervals (RRI) and systolic blood pressure (BPsys) at supine rest and upon standing. We determined mainly sympathetic low (LF) and parasympathetic high (HF) frequency powers of RRI fluctuations, sympathetically mediated LF-BPsys powers, LF/HF-RRI ratios, normalized (nu) LF-RRI and HF-RRI powers, and compared data between groups, at rest and upon standing (ANOVA with post hoc testing). We correlated autonomic parameters with initial Glasgow Coma Scale (GCS) scores (Spearman test; significance: p < 0.05). Supine BPsys and LFnu-RRI powers were higher while HFnu-RRI powers were lower in post-moderate-severe-TBI patients than post-mild-TBI patients and controls. LFnu-RRI powers were higher and HFnu-RRI powers were lower in post-mild-TBI patients than controls. Upon standing, only post-mild-TBI patients and controls increased LF-BPsys powers and BPsys and decreased HF-RRI powers. GCS scores correlated positively with LFnu-RRI powers, LF/HF-RRI ratios, and inversely with HFnu-RRI powers, at standing position. More than 6 months after TBI, there is autonomic dysfunction at rest and upon standing which is more pronounced after moderate-severe than mild TBI and in part correlates with initial trauma severity.

Valsalva maneuver unveils central baroreflex dysfunction with altered blood pressure control in persons with a history of mild traumatic brain injury.

BACKGROUND: Patients with a history of mild TBI (post-mTBI-patients) have an unexplained increase in long-term mortality which might be related to central autonomic dysregulation (CAD). We investigated whether standardized baroreflex-loading, induced by a Valsalva maneuver (VM), unveils CAD in otherwise healthy post-mTBI-patients. METHODS: In 29 healthy persons (31.3 ± 12.2 years; 9 women) and 25 post-mTBI-patients (35.0 ± 13.2 years, 7 women, 4-98 months post-injury), we monitored respiration (RESP), RR-intervals (RRI) and systolic blood pressure (BP) at rest and during three VMs. At rest, we calculated parameters of total autonomic modulation [RRI-coefficient-of-variation (CV), RRI-standard-deviation (RRI-SD), RRI-total-powers], of sympathetic [RRI-low-frequency-powers (LF), BP-LF-powers] and parasympathetic modulation [square-root-of-mean-squared-differences-of-successive-RRIs (RMSSD), RRI-high-frequency-powers (HF)], the index of sympatho-vagal balance (RRI LF/HF-ratios), and baroreflex sensitivity (BRS). We calculated Valsalva-ratios (VR) and times from lowest to highest RRIs after strain (VR-time) as indices of parasympathetic activation, intervals from highest systolic BP-values after strain-release to the time when systolic BP had fallen by 90 % of the differences between peak-phase-IV-BP and baseline-BP (90 %-BP-normalization-times), and velocities of BP-normalization (90 %-BP-normalization-velocities) as indices of sympathetic withdrawal. We compared patient- and control-parameters before and during VM (Mann-Whitney-U-tests or t-tests; significance: P < 0.05). RESULTS: At rest, RRI-CVs, RRI-SDs, RRI-total-powers, RRI-LF-powers, BP-LF-powers, RRI-RMSSDs, RRI-HF-powers, and BRS were lower in patients than controls. During VMs, 90 %-BP-normalization-times were longer, and 90 %-BP-normalization-velocities were lower in patients than controls (P < 0.05). CONCLUSIONS: Reduced autonomic modulation at rest and delayed BP-decrease after VM-induced baroreflex-loading indicate subtle CAD with altered baroreflex adjustment to challenge. More severe autonomic challenge might trigger more prominent cardiovascular dysregulation and thus contribute to increased mortality risk in post-mTBI-patients.

Can stapedius reflex testing objectively measure muscle function in Pompe patients?

We assessed the value of stapedius reflex testing as an objective measurement of striated muscle function in four patients with Pompe disease. Common tests of disease severity and efficacy of enzyme replacement therapy (ERT) yield highly variable results that depend on patient cooperation and day-to-day performance, whereas stapedius reflex thresholds improved in seven of eight ears after 2 years of ERT.

Site and size of multiple sclerosis lesions predict enhanced or decreased female orgasmic function.

Neuroimaging identified brain areas involved in female orgasm. In women with multiple sclerosis (MS), associations between orgasmic function and the site and size of MS-related magnetic resonance imaging (MRI) changes are undetermined. This study intended to correlate MS-associated cerebral lesion load and location with clinical scores of female orgasmic function. In 50 women with MS (mean age 37.0 ± 9.9 years), we assessed Female Sexual Function Index (FSFI) scores for orgasmic frequency, difficulty and satisfaction. We determined disease duration, Expanded Disability Status Scale (EDSS) scores, and cerebral MS-lesion load and location using T2-weighed 1.5 T MRIs. We correlated FSFI scores for orgasm with patient age, disease duration, EDSS scores, and cerebral MS-lesion load (Spearman rank correlation; significance: p < 0.05). FSFI scores for orgasm correlated inversely with MS-lesion load in the left temporal periventricular white matter and right middle-inferior occipital area, but directly with MS-lesion load in the right frontal primary motor cortex, left prefrontal/inferior frontal cortex, right amygdala, left temporal middle-inferior and fusiform areas, and midbrain. FSFI scores for orgasm did not correlate with patient age, disease duration and EDSS scores (p > 0.05). In conclusion, our results indicate that MS-lesions in left temporal periventricular and right visual association areas deteriorate orgasmic function. In contrast, direct correlations between frontotemporal or midbrain lesions and higher FSFI scores, indicating enhanced or disinhibited orgasmic function, suggest that these brain regions normally buffer orgasmic responses. Moreover, our results indicate that orgasmic dysfunction in women with MS evolves independently of disease duration and physical disability.

Erectile dysfunction (ED) after ischemic stroke: association between prevalence and site of lesion.

PURPOSE: Stroke may cause or worsen erectile dysfunction (ED). Post-stroke ED prevalence and association with stroke location are not well established. Therefore, we assessed post-stroke ED prevalence in relation to ischemic lesion locations and stroke severity. METHODS: In 57 men (62.6 ± 10.5 years) who had ischemic stroke within 24 months prior to evaluation, we used the five-item International Index of Erectile Function questionnaire (IIEF5) to evaluate ED prevalence after stroke and retrospectively 3 months prior to stroke. IIEF5 scores range from 5 to 25; scores below 22 indicate ED. We estimated stroke severity upon hospital admission, using the National Institute of Health Stroke Scale (NIHSS), and determined stroke location from cranial computed tomography or magnetic resonance imaging. We compared pre- and post-stroke results with those of 22 control persons (61.7 ± 11.2 years), calculated correlations between IIEF5 scores and NIHSS scores, and compared ED prevalence with stroke locations (significance: p < 0.05). RESULTS: ED was reported by 45/57 patients after stroke, 26/57 patients before stroke, and 6/22 control persons. Patients' IIEF5 values were significantly lower [median 16 interquartile range (IQR) 3.5-20.5] after than before stroke (median 23, IQR 19.0-24.0) and lower than in controls (median 24, IQR 19.8-25.0). Pre- and post-stroke IIEF5 scores did not correlate with the patients' NIHSS scores at stroke onset (p > 0.05). ED was associated with middle cerebral artery infarction in 27/34, posterior cerebral artery infarction in 4/5, anterior cerebral artery infarction in 1/1, basal ganglia infarction in 3/3, brain stem infarction in 8/10, cerebellar infarction in 2/5, and lesions in more than one region in 1/1 patients. CONCLUSIONS: Disruption of the central network assuring erection might contribute to increased ED severity and prevalence after stroke. Anti-erectile effects of functional and psychological impairment or medication added after stroke may also contribute to ED but must be evaluated in larger patients groups.

Central Autonomic Dysfunction Delays Recovery of Fingolimod Induced Heart Rate Slowing.

BACKGROUND: In multiple sclerosis (MS) patients, Fingolimod may induce prolonged heart-rate slowing which might be caused by MS-related central autonomic lesions. OBJECTIVES: To evaluate whether MS-patients with prolonged heart-rate slowing (> six hours) upon Fingolimod show cardiovascular-autonomic dysfunction before Fingolimod-initiation. METHODS: Before Fingolimod-initiation, we recorded electrocardiographic RR-intervals (RRIs) and blood-pressure (BP) at rest, upon standing-up, during metronomic deep-breathing, Valsalva-maneuver, and "sustained-handgrip-exercise" in 21 patients with relapsing-remitting MS, and 20 healthy persons. We calculated sympathetic and parasympathetic cardiovascular parameters, including low- (LF) and high-frequency (HF) powers of RRI- and BP-oscillations, RRI-RMSSDs, RRI- and BP-changes during handgrip-exercise, parasympathetic heart-rate-slowing in relation to BP-overshoot after Valsalva-strain-release. We compared values of healthy persons and patients with and without prolonged heart-rate slowing after Fingolimod-initiation (ANOVA; significance: p<0.05). RESULTS: Upon Fingolimod-initiation, 7/21 patients had prolonged HR-slowing. Before Fingolimod, these patients had higher resting BP and higher BP increase during handgrip-exercise than had the other participants (p<0.05). They did not reduce parasympathetic HR-parameters upon standing-up. After Valsalva-strain-release, their parasympathetic HR-slowing in response to BP-overshoot was four times higher than in the other participants (p<0.05). CONCLUSIONS: The autonomic cardiovascular dysfunction in MS-patients with delayed HR-re-acceleration upon Fingolimod-initiation suggests that MS-related central autonomic lesions compromise HR-re-acceleration upon Fingolimod. TRIAL REGISTRATION: German Clinical Trial Register DRKS00004548 http://drks-neu.uniklinik-freiburg.de/drks_web/setLocale_EN.do.