Efficacy and Tolerability of Intranasal Midazolam Administration for Antiseizure Treatment in Adults: A Systematic Review.

OBJECTIVE: The objective of this study was to assess the efficacy and tolerability of intranasal midazolam (in-MDZ) administration for antiseizure treatment in adults. METHODS: Embase and Medline literature databases were searched. We included randomized trials and cohort studies (excluding case series) of adult patients (≥ 18 years of age) examining in-MDZ administration for epilepsy, epileptic seizures, or status epilepticus published in English between 1985 and 2022. Studies were screened for eligibility based on predefined criteria. The primary outcome was the efficacy of in-MDZ administration, and the secondary outcome was its tolerability. Extracted data included study design, patient characteristics, intervention details, and outcomes. Risk of bias was assessed using the Cochrane Risk of Bias Tool. RESULTS: A total of 12 studies with 929 individuals treated with in-MDZ were included. Most studies were retrospective, with their number increasing over time. Administered in-MDZ doses ranged from 2.5 to 20 mg per single dose. The mean proportion of successful seizure termination after first in-MDZ administration was 72.7% (standard deviation [SD] 18%), and the proportion of seizure recurrence or persistent seizures ranged from 61 to 75%. Most frequent adverse reactions to in-MDZ were dizziness (mean 23.5% [SD 38.6%]), confusion (one study; 17.4%), local irritation (mean 16.6% [SD 9.6%]), and sedation (mean 12.7% [SD 9.7%]). CONCLUSIONS: Administration of in-MDZ seems promising for the treatment of prolonged epileptic seizures and seizure clusters in adults. Limited evidence suggests that intranasal administration is safe. Further research is warranted because of the heterogeneity of cohorts, the variation in dosages, and the lack of uniformity in defining successful seizure termination.

Performance of large language models on advocating the management of meningitis: a comparative qualitative study.

OBJECTIVES: We aimed to examine the adherence of large language models (LLMs) to bacterial meningitis guidelines using a hypothetical medical case, highlighting their utility and limitations in healthcare. METHODS: A simulated clinical scenario of a patient with bacterial meningitis secondary to mastoiditis was presented in three independent sessions to seven publicly accessible LLMs (Bard, Bing, Claude-2, GTP-3.5, GTP-4, Llama, PaLM). Responses were evaluated for adherence to good clinical practice and two international meningitis guidelines. RESULTS: A central nervous system infection was identified in 90% of LLM sessions. All recommended imaging, while 81% suggested lumbar puncture. Blood cultures and specific mastoiditis work-up were proposed in only 62% and 38% sessions, respectively. Only 38% of sessions provided the correct empirical antibiotic treatment, while antiviral treatment and dexamethasone were advised in 33% and 24%, respectively. Misleading statements were generated in 52%. No significant correlation was found between LLMs' text length and performance (r=0.29, p=0.20). Among all LLMs, GTP-4 demonstrated the best performance. DISCUSSION: Latest LLMs provide valuable advice on differential diagnosis and diagnostic procedures but significantly vary in treatment-specific information for bacterial meningitis when introduced to a realistic clinical scenario. Misleading statements were common, with performance differences attributed to each LLM's unique algorithm rather than output length. CONCLUSIONS: Users must be aware of such limitations and performance variability when considering LLMs as a support tool for medical decision-making. Further research is needed to refine these models' comprehension of complex medical scenarios and their ability to provide reliable information.

Association Between Dose Escalation of Anesthetics and Outcomes in Patients With Refractory Status Epilepticus.

BACKGROUND AND OBJECTIVES: To investigate the association between dose escalation of continuously administered IV anesthetics and its duration with short-term outcomes in adult patients treated for refractory status epilepticus (RSE). METHODS: Clinical and electroencephalographic data of patients with RSE without hypoxic-ischemic encephalopathy who were treated with anesthetics at a Swiss academic medical center from 2011 to 2019 were assessed. The frequency of anesthetic dose escalation (i.e., dose increase) and its associations with in-hospital death or return to premorbid neurologic function were primary endpoints. Multivariable logistic regression analysis was performed to identify associations with endpoints. RESULTS: Among 111 patients with RSE, doses of anesthetics were escalated in 57%. Despite patients with dose escalation having a higher morbidity (lower Glasgow Coma Scale [GCS] score at status epilepticus [SE] onset, more presumably fatal etiologies, longer duration of SE and intensive care, more infections, and arterial hypotension) as compared with patients without, the primary endpoints did not differ between these groups in univariable analyses. Multivariable analyses revealed decreased odds for death with dose escalation (odds ratio 0.09, 95% CI 0.01-0.86), independent of initial GCS score, presumably fatal etiology, SE severity score, SE duration, and nonconvulsive SE with coma, with similar functional outcome among survivors compared with patients without dose escalation. DISCUSSION: Our study reveals that anesthetic dose escalation in adult patients with RSE is associated with decreased odds for death without increasing the proportion of surviving patients with worse neurofunctional state than before RSE. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anesthetic dose escalation decreases the odds of death in patients with RSE.

Neurological evolution of severe baclofen intoxication: from brain death mimic to recovered brain function.

Patients with brain death have by definition irreversible and complete loss of brainstem reflexes. Before a definite diagnosis of brain death can be confirmed, all potential confounders must be thoroughly excluded. Baclofen intoxication is a rare cause of brain death mimic characterised by transient deep coma and absence of brainstem reflexes and might be mistaken with brain death. We report the case of a female patient in her 70s who ingested baclofen with suicidal intent and was admitted with a deep coma and loss of all brainstem reflexes and a spontaneous burst-suppression pattern in the electroencephalography which resolved over 10 hours. After a state mimicking brain death for 6 hours, the patient experienced complete recovery. Severe baclofen intoxication can mimic brain death clinically and is associated with temporary pathological electroencephalographic findings. Awareness of this toxidrome is crucial, as appropriate management can lead to full recovery.

The impact of competing stroke etiologies in patients with atrial fibrillation.

BACKGROUND: Data on the impact of competing stroke etiologies in stroke patients with atrial fibrillation (AF) are scarce. METHODS: We used prospectively obtained data from an observational registry (Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-(NOACISP)-LONGTERM) of consecutive AF-stroke patients treated with oral anticoagulants. We compared the frequency of (i) the composite outcome of recurrent ischemic stroke (IS), intracerebral hemorrhage (ICH) or all-cause death as well as (ii) recurrent IS alone among AF-stroke patients with versus without competing stroke etiologies according to the TOAST classification. We performed cox proportional hazards regression modeling adjusted for potential confounders. Furthermore, the etiology of recurrent IS was assessed. RESULTS: Among 907 patients (median age 81, 45.6% female), 184 patients (20.3%) had competing etiologies, while 723 (79.7%) had cardioembolism as the only plausible etiology. During 1587 patient-years of follow-up, patients with additional large-artery atherosclerosis had higher rates of the composite outcome (adjusted HR [95% CI] 1.64 [1.11, 2.40], p = 0.017) and recurrent IS (aHR 2.96 [1.65, 5.35 ], p < 0.001), compared to patients with cardioembolism as the only plausible etiology. Overall 71 patients had recurrent IS (7.8%) of whom 26.7% had a different etiology than the index IS with large-artery-atherosclerosis (19.7%) being the most common non-cardioembolic cause. CONCLUSION: In stroke patients with AF, causes other than cardioembolism as competing etiologies were common in index or recurrent IS. Concomitant presence of large-artery-atherosclerosis seems to indicate an increased risk for recurrences suggesting that stroke preventive means might be more effective if they also address competing stroke etiologies in AF-stroke patients. CLINICAL TRIAL REGISTRATION: NCT03826927.

Association Between Induced Burst Suppression and Clinical Outcomes in Patients With Refractory Status Epilepticus: A 9-Year Cohort Study.

BACKGROUND AND OBJECTIVES: To investigate the frequency of induced EEG burst suppression pattern during continuous IV anesthesia (IVAD) and associated outcomes in adult patients treated for refractory status epilepticus (RSE). METHODS: Patients with RSE treated with anesthetics at a Swiss academic care center from 2011 to 2019 were included. Clinical data and semiquantitative EEG analyses were assessed. Burst suppression was categorized as incomplete burst suppression (with ≥20% and <50% suppression proportion) or complete burst suppression (with ≥50% suppression proportion). The frequency of induced burst suppression and association of burst suppression with outcomes (persistent seizure termination, in-hospital survival, and return to premorbid neurologic function) were the endpoints. RESULTS: We identified 147 patients with RSE treated with IVAD. Among 102 patients without cerebral anoxia, incomplete burst suppression was achieved in 14 (14%) with a median of 23 hours (interquartile range [IQR] 1-29) and complete burst suppression was achieved in 21 (21%) with a median of 51 hours (IQR 16-104). Age, Charlson comorbidity index, RSE with motor symptoms, the Status Epilepticus Severity Score and arterial hypotension requiring vasopressors were identified as potential confounders in univariable comparisons between patients with and without any burst suppression. Multivariable analyses revealed no associations between any burst suppression and the predefined endpoints. However, among 45 patients with cerebral anoxia, induced burst suppression was associated with persistent seizure termination (72% without vs 29% with burst suppression, p = 0.004) and survival (50% vs 14% p = 0.005). DISCUSSION: In adult patients with RSE treated with IVAD, burst suppression with ≥50% suppression proportion was achieved in every fifth patient and not associated with persistent seizure termination, in-hospital survival, or return to premorbid neurologic function.

Doublecortin and Glypican-2 concentrations in the cerebrospinal fluid from infants are developmentally downregulated.

OBJECTIVE: Doublecortin (DCX) and glypican-2 (GPC2) are neurodevelopmental proteins involved in the differentiation of neural stem/progenitor cells (NSPCs) to neurons, and are developmentally downregulated in neurons after birth. In this study, we investigated whether the concentrations of DCX and GPC2 in the cerebrospinal fluid (CSF) from human pediatric patients reflect this developmental process or are associated with cerebral damage or inflammatory markers. METHODS: CSF was collected from pediatric patients requiring neurosurgical treatment. The concentrations of DCX, GPC2, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B), and cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, and TNF-⍺) were measured using immunoassays. RESULTS: From March 2013 until October 2018, 63 CSF samples were collected from 38 pediatric patients (20 females; 17 patients with repeated measurements); the median term born-adjusted age was 3.27 years [Q1: 0.31, Q3: 7.72]. The median concentration of DCX was 329 pg/ml [Q1: 192.5, Q3: 1179.6] and that of GPC2 was 26 pg/ml [Q1: 13.25, Q3: 149.25]. DCX and GPC2 concentrations independently significantly associated with age, and their concentration declined with advancing age, reaching undetectable levels at 0.3 years for DCX, and plateauing at 1.5 years for GPC2. Both DCX and GPC2 associated with hydrocephalus, NSE, IL-1ß, IL-2, IL-8, IL-13. No relationship was found between sex, acute infection, S100B, IL-4, IL-6, IL-10, IFN-γ, TNF-α and DCX or GPC2, respectively. CONCLUSIONS: Concentrations of DCX and GPC2 in the CSF from pediatric patients are developmentally downregulated, with the highest concentrations measured at the earliest adjusted age, and reflect a neurodevelopmental stage rather than a particular disease state.

Global Cortical Atrophy Is Associated with an Unfavorable Outcome in Stroke Patients on Oral Anticoagulation.

INTRODUCTION: Measures of cerebral small vessel disease (cSVD), such as white matter hyperintensities (WMH) and cerebral microbleeds (CMB), are associated with an unfavorable clinical course in stroke patients on oral anticoagulation (OAC) for atrial fibrillation (AF). Here, we investigated whether similar findings can be observed for global cortical atrophy (GCA). METHODS: Registry-based prospective observational study of 320 patients treated with OAC following AF stroke. Patients underwent magnetic resonance imaging (MRI) allowing assessment of GCA. Using the simplified visual Pasquier scale, the severity of GCA was categorized as follows: 0: no atrophy, 1: mild atrophy; 2: moderate atrophy, and 3: severe atrophy. Using adjusted logistic and Cox regression analysis, we investigated the association of GCA using a composite outcome measure, comprising: (i) recurrent acute ischemic stroke (IS); (ii) intracranial hemorrhage (ICH); and (iii) death. RESULTS: In our time to event analysis after adjusting for potential confounders (i.e., WMH, CMB, age, sex, diabetes, arterial hypertension, coronary heart disease, hyperlipidemia, and antiplatelet use), GCA was associated with an increased risk for the composite outcome in all three degrees of atrophy (grade 1: aHR 3.95, 95% CI 1.34-11.63, p = 0.013; grade 2: aHR 3.89, 95% CI 1.23-12.30, p = 0.021; grade 3: aHR 4.16, 95% CI 1.17-14.84, p = 0.028). CONCLUSION: GCA was associated with our composite outcome also after adjusting for other cSVD markers (i.e., CMB, WMH) and age, indicating that GCA may potentially serve as a prognostic marker for stroke patients with atrial fibrillation on oral anticoagulation.

Balancing the risks and benefits of anesthetics in status epilepticus.

PURPOSE: According to international guidelines, status epilepticus refractory to first- and second-line antiseizure medication should be treated with anesthetics. Therefore, continuously delivered intravenous midazolam, propofol, or barbiturates are recommended as third-line therapy. While electroencephalographically (EEG)-controlled titration of anesthetics to seizure termination or to the emergence of an EEG burst-suppression pattern makes sense, evidence of the efficacy and tolerability of such third-line treatment is limited and concerns regarding the risks of anesthesia remain. The lack of treatment alternatives and persistent international discord reflecting contradictory results from some studies leave clinicians on their own when deciding to escalate treatment. In this conference-accompanying narrative review, we highlight the challenges of EEG-monitored third-line treatment and discuss recent studies that examined earlier administration of anesthetics. RESULTS: Based on the literature, maintaining continuous burst suppression is difficult despite the constant administration of anesthetics, and the evidence for burst suppression as an adequate surrogate target is limited by methodological shortcomings as acknowledged by international guidelines. In our Swiss cohort including 102 patients with refractory status epilepticus, burst suppression as defined by the American Clinical Neurophysiology Society's Critical Care EEG Terminology 2021 was established in only 21%. Besides case reports suggesting that rapid but short-termed anesthesia can be sufficient to permanently stop seizures, a study including 205 patients revealed that anesthesia as second-line treatment was associated with a shorter median duration of status epilepticus (0.5 versus 12.5 days, p < 0.001), median ICU (2 versus 5.5 days, p < 0.001) and hospital stay (8 versus 17 days, p < 0.001) with equal rates of complications when compared to anesthesia as third-line treatment. CONCLUSIONS: Recent investigations have led to important findings and new insights regarding the use of anesthetics in refractory status epilepticus. However, numerous methodological limitations and remaining questions need to be considered when it comes to the translation into clinical practice, and, in consequence, call for prospective randomized studies. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Impact of type of oral anticoagulants in patients with cerebral microbleeds after atrial fibrillation-related ischemic stroke or TIA: Results of the NOACISP-LONGTERM registry.

Background: Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC). Methods: Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists [VKAs] vs. direct oral anticoagulants [DOACs]) with clinical outcome. Results: Of 310 AF-stroke patients treated with OAC [DOACs: n = 234 (75%); VKAs: n = 76 (25%)], CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 [1.614; 8.277]; p = 0.002; DOACs: HR 2.230 [1.233; 4.034]; p = 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups [VKAs 13/20(65%) vs. DOACs 19/66(29%); p < 0.01]. The VKA-group had a 2-fold higher IS [VKAs:4 (20%) vs. DOACs:6 (9%); p = 0.35] and a 10-fold higher ICH rate [VKAs: 3 (15%) vs. DOACs: 1 (1.5%); p = 0.038]. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 [0.17; 0.94]; p = 0.04). Conclusions: In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs. Clinical trial registration: http://www.clinicaltrials.gov, Unique identifier: NCT03826927.

Oral Anticoagulants in Atrial Fibrillation Patients With Recent Stroke Who Are Dependent on the Daily Help of Others.

Background and Purpose: Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. Methods: Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome­the composite of recurrent ischemic stroke, major bleeding, and all-cause death­among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3­5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. Results: We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42­0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40­0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HRdependent, 0.68 [95% CI, 0.45­1.01]) and independent patients (HRindependent, 0.44 [95% CI, 0.26­0.75]) in the simple model (Pinteraction=0.212). Adjusted (HRdependent, 0.74 [95% CI, 0.49­1.11] and HRindependent, 0.51 [95% CI, 0.30­0.87]; Pinteraction=0.284) and weighted models (HRdependent, 0.79 [95% CI, 0.48­1.31] and HRindependent, 0.46 [95% CI, 0.26­0.81]; Pinteraction=0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. Conclusions: The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03826927.

Editor's Choice - Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

OBJECTIVE: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed. METHODS: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation. RESULTS: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019). CONCLUSION: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.

Accuracy of Calculated Free Valproate Levels in Adult Patients With Status Epilepticus.

OBJECTIVE: To test the accuracy of an equation in adult patients with status epilepticus that calculates the free concentration of serum valproic acid (fVPA) from the total concentration of serum valproic acid (tVPA) and serum albumin. METHODS: All adult patients with status epilepticus who were treated at a Swiss academic medical center between 2005 and 2018 with concurrent measurements of tVPA, fVPA, and serum albumin were included. fVPA was categorized as subtherapeutic, therapeutic (5-10 mg/L), or supratherapeutic. Agreement was defined as the proportion of measured and calculated fVPA falling within the same category. RESULTS: Of 676 patients with status epilepticus, 104 had 506 measurements, with a median of 3 (interquartile range [IQR] 1.5-6.5) per patient. The median tVPA was 43.5 mg/L (27.4-63.6), with measured fVPA 9.1 mg/L (4.5-14.7) and calculated fVPA 10.1 mg/L (7.0-13.0), respectively. The median deviation of calculated from measured fVPA was -0.8 mg/L (-3.2 to 2.5) with 336 measurements >1 mg/L. While the association between measured and calculated fVPA was linear (regression coefficient 1.1, 95% confidence interval 0.9-1.2, p < 0.0001), the agreement on effective drug levels did not match in 39.8% of measurements regardless of serum albumin levels, with calculated fVPA overestimating measured fVPA in 30.4%. tVPA and serum albumin independently influenced the accuracy of the calculated fVPA in the multivariable model. CONCLUSIONS: Calculated fVPA is inaccurate when using the proposed equation in adult patients with status epilepticus, calling for drug monitoring based on measured fVPA in this context.

Neonatal hypoxia-ischemia in rat elicits a region-specific neurotrophic response in SVZ microglia.

BACKGROUND: Recent findings describe microglia as modulators of neurogenesis in the subventricular zone (SVZ). SVZ microglia in the adult rat are thought to adopt a neurotrophic phenotype after ischemic stroke. Early postnatal microglia are endogenously activated and may therefore exhibit an increased sensitivity to neonatal hypoxia-ischemia (HI). The goal of this study was to investigate the impact of cortico-striatal HI on the microglial phenotype, function, and gene expression in the early postnatal SVZ. METHODS: Postnatal day (P)7 rats underwent sham or right-hemispheric HI surgery. Microglia in the SVZ, the uninjured cortex, and corpus callosum were immunohistochemically analyzed at P10, P20, and P40. The transcriptome of microdissected SVZ and cortical microglia was analyzed at P10 and P20, and the effect of P10 SVZ microglia on neurosphere generation in vitro was studied. RESULTS: The microglial response to HI was region-specific. In the SVZ, a microglial accumulation, prolonged activation and phagocytosis was noted that was not observed in the cortex and corpus callosum. The transcriptome of SVZ microglia and cortical microglia were distinct, and after HI, SVZ microglia concurrently upregulated pro- and anti-inflammatory as well as neurotrophic genes. In vitro, microglia isolated from the SVZ supported neurosphere generation in a concentration-dependent manner. CONCLUSIONS: Microglia are an inherent cellular component of the early postnatal SVZ and undergo developmental changes that are affected on many aspects by neonatal HI injury. Our results demonstrate that early postnatal SVZ microglia are sensitive to HI injury and display a long-lasting region-specific response including neurotrophic features.

Impact of parturition on maternal cardiovascular and neuronal integrity in a high risk cohort - a prospective cohort study.

BACKGROUND: To better understand the profound multisystem changes in maternal physiology triggered by parturition, in particular in the underexplored neuronal system, by deploying a panel of pre- vs post-delivery maternal serum biomarkers, most notably the neuronal cytoskeleton constituent neurofilament light chain (NfL). This promising fluid biomarker is not only increasingly applied to investigate disease progression in numerous brain diseases, particularly in proteopathies, but also in detection of traumatic brain injury or monitoring neuroaxonal injury after ischemic stroke. METHODS: The study was nested within a prospective cohort study of pregnant women at risk of developing preeclampsia at the University Hospital of Basel. Paired ante- and postpartum levels of progesterone, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin (CT-proAVP), and NfL were measured in 56 women with complete clinical data. RESULTS: Placental delivery significantly decreased all placental markers: progesterone 4.5-fold, PlGF 2.2-fold, and sFlt-1 1.7-fold. Copeptin and MR-proANP increased slightly (1.4- and 1.2-fold, respectively). Unexpectedly, NfL levels (median [interquartile range]) increased significantly post-partum: 49.4 (34.7-77.8) vs 27.7 (16.7-31.4) pg/ml (p < 0.0001). Antepartum NfL was the sole independent predictor of NfL peri-partum change; mode of delivery, duration of labor, clinical characteristics and other biomarkers were all unrelated. Antepartum NfL levels were themselves independently predicted only by maternal age. CONCLUSIONS: Parturition per se increases maternal serum NfL levels, suggesting a possible impact of parturition on maternal neuronal integrity.