Evaluating the utility of serum NfL, GFAP, UCHL1 and tTAU as estimates of CSF levels and diagnostic instrument in neuroinflammation and multiple sclerosis.

BACKGROUND: This study aimed to evaluate the utility of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL1) and total tau (tTAU) serum concentrations as approximation for cerebrospinal fluid (CSF) concentrations of the respective biomarkers in the context of neuroinflammation and multiple sclerosis (MS). METHODS: NfL, GFAP, UCHL1 and tTAU concentrations in serum and CSF were measured in 183 patients (122 with neuroinflammatory disease and 61 neurological or somatoform disease controls) using the single molecule array HD-1 analyzer (Quanterix, Boston, MA). Spearman's rank correlations were computed between serum and CSF concentrations. In a second step, the effects of age, BMI, gadolinium-enhancing lesions in MRI, integrity of the blood-brain barrier (BBB) and presence of acute relapse were accounted for by computing partial correlations. The analyses were repeated for a subsample consisting of MS phenotype patients only (n = 118). EDSS, MS disease activity and acute relapse were considered as additional covariates. Receiver operating characteristic (ROC) analysis was performed for each serum/CSF biomarker concentration to assess how well the particular biomarker concentration differentiates MS patients from somatoform disease controls. Correlations between serum and CSF levels as well as area under the curve (AUC) values were compared for the different biomarkers using z-test statistics. RESULTS: Serum concentrations correlated positively with CSF levels for NfL (r = 0.705, p < 0.01) as well as for GFAP (r = 0.259, p < 0.01). Correlation coefficients were significantly higher for NfL than for GFAP (z = 5.492, p < 0.01). We found no significant serum-CSF correlations for UCHL1 or tTAU. After adjusting for covariates, the results remained unchanged. In the analysis focusing only on MS patients, the results were replicated. ROC analysis demonstrated similarly acceptable performance of serum and CSF NfL values in differentiating MS phenotype patients from somatoform disease controls. AUC values were significantly higher for serum and CSF NfL compared to other biomarkers. CONCLUSION: NfL and GFAP but not UCHL1 or tTAU serum concentrations are associated with CSF levels of the respective biomarker. NfL exhibits more robust correlations between its serum and CSF concentrations as compared to GFAP independently from BBB integrity, clinical and radiological covariates. Both serum and CSF NfL values differentiate between MS and controls.

Matching proposed clinical and MRI criteria of aggressive multiple sclerosis to serum and cerebrospinal fluid markers of neuroaxonal and glial injury.

BACKGROUND: Definitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP)). METHODS: We recruited 77 patients with relapsing-remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse. RESULTS: After adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.00008; pcNfL = 0.004) as well as the presence of infratentorial lesions on MRI (psNfL = 0.0003; pcNfL < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.001), presence of more than 20 T2-lesions (psNfL = 0.049) as well as the presence of infratentorial lesions on MRI (psNfL = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.011) and presence of more than 20 T2-lesions (psNfL = 0.029). CONCLUSIONS: Among proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone.

Large-vessel-occlusion in patients with previous ischemic stroke: an analysis of adherence to secondary preventive medication for different etiologies.

BACKGROUND: Large vessel occlusion (LVO) is a severe condition that carries a high risk of morbidity and mortality, underscoring the importance of effective prevention strategies. This retrospective study aimed to analyze the intake of preventive medication at the time of hospitalization in a cohort of recurrent stroke patients presenting with acute LVO. METHODS: The study assessed the intake of either platelet aggregation inhibitors (PAI), oral anticoagulants (OAC) or statins at admission in patients with recurrent stroke and correlated it with the final classification of LVO. The frequency of those secondary preventive medication in recurrent stroke patients was defined as primary endpoint. The Modified Rankin Scale (mRS) at discharge was used as a functional outcome and defined as a secondary outcome measure. RESULTS: This study included 866 patients who were treated for LVO between 2016 and 2020, of whom 160 (18.5%) had a recurrent ischemic stroke. OAC (25.6% vs. 14.1%, p < 0.01), PAI (50.0% vs. 26.0%, p < 0.01), or statin therapy (50.6% vs. 20.8%, p < 0.01) at admission were significantly more frequent in recurrent stroke patients compared to patients with a first-time stroke. Concerning LVO etiology in recurrent stroke patients, OAC at admission was taken in 46.8% of cardioembolic LVO, whereas PAI and statin at admission in macroangiopathic LVO were administered to 40.0%; neither PAI nor OAC was taken in 26.0%, 28.3%, and 31.6% of cardioembolic, macroangiopathic, or cryptogenic strokes, respectively. Regardless of stroke recurrence or etiology, there was an increase in mRS at discharge. CONCLUSIONS: Despite high-quality healthcare, this study suggested a significant proportion of patients with recurrent stroke who were either non-adherent or insufficiently adherent to secondary preventive medication. Given the disability associated with LVO, improving patients' medication adherence and identifying unknown stroke causes are crucial for effective prevention strategies.

Serum and cerebrospinal fluid BDNF concentrations are associated with neurological and cognitive improvement in multiple sclerosis: A pilot study.

BACKGROUND: Biomarkers of disease activity have been intensively studied in multiple sclerosis (MS) but knowledge on predictors of disability improvement is limited. The aim of this pilot study was to explore whether increased brain-derived neurotrophic factor concentrations in serum and CSF (sBDNF/cBDNF) precede neurological and cognitive improvement in MS. METHODS: In this pilot, monocentric prospective cohort study we collected serum/CSF samples at baseline together with EDSS (n = 36) and cognitive testing (n = 34) in patients with relapsing-remitting/primary progressive MS or clinically isolated syndrome. BDNF was assessed in serum and CSF with a single molecule array (SIMOA) HD-1 analyser (Quanterix). Twelve months later EDSS and cognitive testing were repeated. BDNF concentrations of patients with vs. without disability or cognitive improvement (disability improvement: decrease in EDSS ≥ 0.5; cognitive improvement: average z-score increase in neuropsychological performance ≥ 0.5) were compared using univariate ANOVAs adjusting for covariates. RESULTS: Compared to subjects without, patients with disability improvement had higher sBDNF at baseline (q = 0.04). Subjects with cognitive improvement had higher cBDNF at baseline than those without cognitive improvement (q = 0.004). Secondary analysis demonstrated significant correlations between sBDNF and EDSS change (q = 0.036), cBDNF and average z-score change (q = 0.04) and cBDNF and number of cognitive tests with improvement (q = 0.04), while controlling for covariates. CONCLUSIONS: Our findings suggest a possible role for BDNF in neurological and cognitive improvement in MS. These findings have to be confirmed in a larger sample but they already highlight the potential of BDNF as a biomarker for disability improvement and neuroplasticity in MS.

Effect of Estimated Blood Volume and Body Mass Index on GFAP and NfL Levels in the Serum and CSF of Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To increase the validity of biomarker measures in multiple sclerosis (MS), factors affecting their concentration need to be identified. Here, we test whether the volume of distribution approximated by the patients' estimated blood volume (BV) and body mass index (BMI) affect the serum concentrations of glial fibrillary acidic protein (GFAP). As a control, we also determine the relationship between BV/BMI and GFAP concentrations in CSF. To confirm earlier findings, we test the same hypotheses for neurofilament light chain (NfL). METHODS: NfL and GFAP concentrations were measured in serum and CSF (sNFL/sGFAP and cNFL/cGFAP) in 157 patients (n = 106 with MS phenotype and n = 51 with other neurologic/somatoform diseases). Using multivariate linear regressions, BV was tested in the MS cohort as a predictor for each of the biomarkers while controlling for age, sex, MS phenotype, Expanded Disability Status Scale score, gadolinium-enhancing lesions, and acute relapse. In addition, overweight/obese patients (BMI ≥25 kg/m2) were compared with patients with BMI <25 kg/m2 using the general linear model. The analyses were repeated including the neurologic/somatoform controls. RESULTS: In the MS cohort, BV predicted sGFAP (ß = -0.301, p = 0.014). Overweight/obese patients with MS had lower sGFAP concentrations compared with patients with MS and BMI <25 kg/m2 (F = 4.732, p = 0.032). Repeating the analysis after adding patients with other neurologic/somatoform diseases did not change these findings (ß = -0.276, p = 0.009; F = 7.631, p = 0.006). Although sNfL was inversely correlated with BV (r = -0.275, p = 0.006) and body weight (r = -0.258, p = 0.010), those results did not remain significant after adjusting for covariates. BV and BMI were not associated with cGFAP or cNfL concentrations. DISCUSSION: These findings support the notion that the volume of distribution of sGFAP approximated by BV and BMI is a relevant variable and should therefore be controlled for when measuring sGFAP in MS, while this might not be necessary when measuring cGFAP concentrations.

Benzodiazepines in the Management of Seizures and Status Epilepticus: A Review of Routes of Delivery, Pharmacokinetics, Efficacy, and Tolerability.

Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA)A receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.

Predictive Factors of Acute Symptomatic Seizures in Patients With Ischemic Stroke Due to Large Vessel Occlusion.

Introduction: Acute symptomatic seizures (ASz) after ischemic stroke are associated with increased mortality; therefore, identifying predictors of ASz is important. The purpose of this study was to analyze predictors of ASz in a population of patients with ischemic stroke due to large arterial vessel occlusion (LVO). Materials and Methods: This retrospective study examined patients with acute ischemic stroke caused by LVO between 2016 and 2020. Identification of predictive factors was performed using univariate and subsequent multiple logistic regression analysis. In addition, subgroup analysis regarding seizure semiology and time of seizure occurrence (≤ 24 h and > 24 h after stroke) was performed. Results: The frequency of ASz among 979 patients was 3.9 % (n = 38). Univariate logistic regression analysis revealed an increased risk of ASz in patients with higher National Institutes of Health Stroke Scale (NIHSS) score at admission or 24 h after admission, hypernatremia at admission ≥ 145 mmol/L, and pneumonia. Further multiple logistic regression analysis revealed that NIHSS 24 h after admission was the strongest predictor of ASz, particularly relating to ASz occurring later than 24 h after stroke. Patients who experienced a seizure within the first 24 h after stroke were more likely to have a generalized tonic-clonic (GTCS) and focal motor seizure; beyond 24 h, seizures with impaired awareness and non-convulsive status epilepticus were more frequent. Conclusion: NIHSS score 24 h after admission is a strong predictive factor for the occurrence of ASz in patients with ischemic stroke caused by LVO. The semiology of ASz varied over time, with GTCS occurring more frequently in the first 24 h after stroke.

Brain-derived neurotrophic factor and neurofilament light chain in cerebrospinal fluid are inversely correlated with cognition in Multiple Sclerosis at the time of diagnosis.

BACKGROUND: Cognitive performance may be impaired in MS even at the earliest stages of disease. We tested whether brain-derived neurotrophic factor and neurofilament light chain levels in serum and cerebrospinal fluid (CSF) samples (sNfL/cNfL/sBDNF/cBDNF) collected at the time of diagnosis are associated with cognitive performance. METHODS: We measured sNfL/cNfL/sBDNF/cBDNF using single-molecule array (Simoa) in 47 newly diagnosed patients (32 relapsing-remitting MS/6 primary progressive MS/9 clinically isolated syndrome). Partial correlations between average z-score on neuropsychological tests and sNfL/sBDNF/cNfL/cBDNF were computed after adjusting for covariates. Multivariate analysis of covariance determined the effect of cognitive status on biomarker levels. A composite measure of NfL and BDNF was submitted to similar exploratory analysis. RESULTS: Cognitive performance correlated inversely with cNfL (r=-0.451/q=0.032) and cBDNF (r=-0.406/q=0.034). Impairment in at least two different tests was linked to higher cNfL (p=0.011) and cBDNF (p=0.035) levels compared to impairment in only one test and for cNfL also compared to no impairment at all (p=0.01). Composite CSF biomarker measure accounting for both cNfL and cBDNF correlated more strongly with tests of information processing (p=0.048) and verbal learning/memory consolidation (p = 0.02) as compared to the single CSF biomarkers. CONCLUSIONS: CSF BDNF and NfL levels measured at the time of diagnosis are inversely associated with cognitive performance in MS. Our findings suggest that CSF biomarkers linked to different pathophysiological processes reflect neuropsychological impairment in the earliest stages of the disease. Combining different CSF measures might facilitate the developing of a better biomarker of cognition in MS.

Patterns of intracerebral hemorrhage that result in unfavorable outcomes in patients with subarachnoid hemorrhage.

OBJECTIVE(S): Intracerebral hemorrhage (ICH) contributes considerably to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH). Specific patterns of aSAH-associated ICH that are not compatible with favorable outcome remain unknown. The main objective of this study is to report patterns of aSAH-associated ICH that result in unfavorable outcomes. METHODS: This is a retrospective analysis of 1036 consecutive aSAH patients admitted to an academic neurosurgical center in a 15-year period (01/2005-12/2019). Admission imaging was investigated for presence, location and size of intracerebral hemorrhage. The rates of favorable outcome at 6 months (modified Rankin Scale) relative to ICH location and volume were analyzed to identify patterns of ICH which were incompatible with favorable outcome. RESULTS: 284 of 1036 patients (27.4%) suffered from aSAH-related ICH. The median ICH volume was 14.0 ml. Outcome of patients with ICH < 10 ml was comparable to patients without ICH. ICH volumes > 10 ml were associated with worse outcomes. We identified the fronto-basal brain to tolerate even larger ICH without compromise of neurological outcomes. ICH located in the frontal, fronto-insular, temporo-insular and temporal regions were associated with intermediate prognoses as outcome declined with larger ICH volumes. ICH located in the basal ganglia, cerebellum, corpus callosum and bifrontal ICH were associated with particularly poor outcomes irrespective of ICH volumes. CONCLUSION: aSAH-associated ICH of the basal ganglia, cerebellum, corpus callosum and bifrontal brain are associated with exceptionally poor outcomes. ICH volume alone is insufficient for prognostic considerations.

SARS-CoV-2-related rapid reorganization of an epilepsy outpatient clinic from personal appointments to telemedicine services: A German single-center experience.

INTRODUCTION: When the SARS-CoV-2 pandemic reached Europe in 2020, a German governmental order forced clinics to immediately suspend elective care, causing a problem for patients with chronic illnesses such as epilepsy. Here, we report the experience of one clinic that converted its outpatient care from personal appointments to telemedicine services. METHODS: Documentations of telephone contacts and telemedicine consultations at the Epilepsy Center Frankfurt Rhine-Main were recorded in detail between March and May 2020 and analyzed for acceptance, feasibility, and satisfaction of the conversion from personal to telemedicine appointments from both patients' and medical professionals' perspectives. RESULTS: Telephone contacts for 272 patients (mean age: 38.7 years, range: 17-79 years, 55.5% female) were analyzed. Patient-rated medical needs were either very urgent (6.6%, n = 18), urgent (23.5%, n = 64), less urgent (29.8%, n = 81), or nonurgent (39.3%, n = 107). Outpatient service cancelations resulted in a lack of understanding (9.6%, n = 26) or anger and aggression (2.9%, n = 8) in a minority of patients, while 88.6% (n = 241) reacted with understanding, or relief (3.3%, n = 9). Telemedicine consultations rather than a postponed face-to-face visit were requested by 109 patients (40.1%), and these requests were significantly associated with subjective threat by SARS-CoV-2 (p = 0.004), urgent or very urgent medical needs (p = 0.004), and female gender (p = 0.024). Telemedicine satisfaction by patients and physicians was high. Overall, 9.2% (n = 10) of patients reported general supply problems due to SARS-CoV-2, and 28.4% (n = 31) reported epilepsy-specific problems, most frequently related to prescriptions, or supply problems for antiseizure drugs (ASDs; 22.9%, n = 25). CONCLUSION: Understanding and acceptance of elective ambulatory visit cancelations and the conversion to telemedicine consultations was high during the coronavirus disease 2019 (COVID-19) lockdown. Patients who engaged in telemedicine consultations were highly satisfied, supporting the feasibility and potential of telemedicine during the COVID-19 pandemic and beyond.

Functional Outcome Following Stroke Thrombectomy in Clinical Practice.

Background and Purpose- Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods- Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0-2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results- Median age was 75 years (interquartile range, 64-82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10-19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions (P=0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05-1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03-1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08-1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15-1.39), alteplase use (OR, 1.49; 95% CI, 1.08-2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45-1.96). Conclusions- High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03356392.