Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis.

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1ß (IL-1ß) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1ß release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis.

Influence of androgens on the innate immune system.

BACKGROUND: Sexual dimorphism is observed in the occurrence, course, and severity of human disease. The difference in immune response between males and females can in part be attributed to sexual genotype. However, immunological differences can also be explained by endocrine-immune interactions. Specifically, androgens possess the ability of directly modulating the development and function of immune cells. Although androgens generally contribute to immunosuppressive effects, this is not necessarily always the case. AIM: The aim of the review is to uncover the role of androgens in shaping the innate immune response. MATERIAL & METHODS: Authors included papers in this review which discussed the impact of androgens on specific innate immune cells. RESULTS: Androgens modulate the innate immune response through various mechanisms. However, there is conflicting evidence in the literature regarding the interplay betwen androgens and the innate immune system. DISCUSSION: Conflicting evidence presented in this review could in part be explained by the limitations present in interpreting results. CONCLUSION: This review is of great importance for our understanding of occurence and mechanism of human inflammatory disease.

Perinatal inflammation exposure and developmental outcomes 7 years after neonatal arterial ischaemic stroke.

AIM: To test the association between perinatal inflammation exposure and Full-Scale IQ (FSIQ) score 7 years after neonatal arterial ischaemic stroke (NAIS). METHOD: We conducted a cross-sectional ancillary study nested in a multicentric longitudinal French cohort of infants born at term with NAIS between November 2003 and October 2006. Seventy-three children were included (45 males, 28 females). The a priori defined primary outcome measure was the FSIQ score assessed with the Wechsler Intelligence Scale for Children, Fourth Edition at 7 years of age. RESULTS: Seventeen (23%) of the included children were exposed to perinatal inflammation. Exposure to perinatal inflammation was independently associated with an increase of FSIQ score (coefficient 13.4, 95% confidence interval 1.3-25.4; p = 0.03). Children exposed to perinatal inflammation had a higher median cerebral volume, a lower median lesion volume, and less extensive lesion distributions compared to non-exposed children. INTERPRETATION: We propose the existence of two NAIS categories: arteritis-associated NAIS in children exposed to perinatal inflammation and embolism-associated NAIS in children non-exposed to perinatal inflammation. Identifying these two NAIS categories would open the possibility for specific curative strategies: anti-inflammatory strategy in arteritis-associated NAIS and recanalization strategy in embolism-associated NAIS.

Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Necroptosis Blockade Potentiates the Neuroprotective Effect of Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy.

Neonatal encephalopathy (NE) caused by hypoxia-ischemia (HI) affects around 1 per 1000 term newborns and is the leading cause of acquired brain injury and neurodisability. Despite the use of hypothermia (HT) as a standard of care, the incidence of NE and its devastating outcomes remains a major issue. Ongoing research surrounding add-on neuroprotective strategies against NE is important as HT effects are limited, leaving 50% of treated patients with neurological sequelae. Little is known about the interaction between necroptotic blockade and HT in neonatal HI. Using a preclinical Lewis rat model of term human NE induced by HI, we showed a neuroprotective effect of Necrostatin-1 (Nec-1: a compound blocking necroptosis) in combination with HT. The beneficial effect of Nec-1 added to HT against NE injuries was observed at the mechanistic level on both pMLKL and TNF-α, and at the anatomical level on brain volume loss visualized by magnetic resonance imaging (MRI). HT alone showed no effect on activated necroptotic effectors and did not preserve the brain MRI volume. This study opens new avenues of research to understand better the specific cell death mechanisms of brain injuries as well as the potential use of new therapeutics targeting the necroptosis pathway.

Protective Effects of Interleukin-1 Blockade on Group B Streptococcus-Induced Chorioamnionitis and Subsequent Neurobehavioral Impairments of the Offspring.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. Placental infection due to GBS is a major risk factor for fetal organ injuries, preterm birth, perinatal morbidity and mortality, and life-long multiorgan morbidities. Preclinical and clinical studies have shown that GBS-induced infection drives polymorphonuclear (PMN) cell infiltration within the placenta, the hallmark of human chorioamnionitis. In preclinical and clinical studies, the upregulation of interleukin(IL)-1ß in the placenta and maternal/fetal blood was associated with a high risk of neurodevelopmental impairments in the progeny. We hypothesized that targeted IL-1 blockade administered to the dam alleviates GBS-induced chorioamnionitis and the downstream fetal inflammatory response syndrome (FIRS). IL-1 receptor antagonist (IL-1Ra) improved the gestational weight gain of GBS-infected dams and did not worsen the infectious manifestations. IL-1Ra reduced the IL-1ß titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1ß titer in the fetal sera of GBS-exposed fetuses. IL-1 blockade also alleviated GBS-induced FIRS and subsequent neurobehavioral impairments of the offspring without worsening the outcome of GBS infection. Altogether, these results showed that IL-1 plays a key role in the physiopathology of live GBS-induced chorioamnionitis and consequent neurobehavioral impairments.

Androgens Upregulate Pathogen-Induced Placental Innate Immune Response.

Group B Streptococcus (GBS) is a leading cause of placental infection, termed chorioamnionitis. Chorioamnionitis is associated with an increased risk of neurobehavioral impairments, such as autism spectrum disorders, which are more prominent in males than in female offspring. In a pre-clinical model of chorioamnionitis, a greater inflammatory response was observed in placenta associated with male rather than female fetuses, correlating with the severity of subsequent neurobehavioral impairments. The reason for this sex difference is not understood. Our hypothesis is that androgens upregulate the placental innate immune response in male fetuses. Lewis dams were injected daily from gestational day (G) 18 to 21 with corn oil (vehicle) or an androgen receptor antagonist (flutamide). On G 19, dams were injected with saline (control) or GBS. Maternal, fetal sera and placentas were collected for protein assays and in situ analyses. Our results showed that while flutamide alone had no effect, a decrease in placental concentration of pro-inflammatory cytokines and infiltration of polymorphonuclear cells was observed in flutamide/infected compared to vehicle/infected groups. These results show that androgens upregulate the placental innate immune response and thus may contribute to the skewed sex ratio towards males observed in several developmental impairments resulting from perinatal infection/inflammation.

Quality of life in pediatric-onset multiple sclerosis: Different disease course, different impact, different measurement approach needed.

OBJECTIVE: To understand the impact of pediatric multiple sclerosis (MS), health-related quality of life (HRQL) measures have been used. However, specific areas of concern of youths with MS are not known. The objective of this study was to contribute content for inclusion in a new condition-specific measure of the life impact of MS for children and adolescents. METHODS: A patient engagement framework was used, and an online survey was developed using the Patient Generated Index (PGI). Text threads generated by the PGI were mapped to the International Classification of Functioning, Disability, and Health (ICF) and the Comprehensive ICF Core Set for MS. RESULTS: A total of 20 people completed the PGI survey of which 11 were youths with MS aged 14 to 22 years. Over 75% of the areas nominated by youths with MS were related to activities and participation and approximately 20% were related to body function. In contrast, 60% of the areas nominated by parents were related to body function. This finding indicated that a measure of life impact would need to include both impairments associated with MS and important activities and roles. This new approach has a disability component covers MS-related impairments and is completed using the PGI system where the youth select disability areas affected by MS, rate, and prioritize each area for improvement. The "quality of life" component queries those areas that are going well. CONCLUSION: This new measurement approach could prove useful in overcoming challenges in developing condition-specific measures for rare conditions.

Animal Models of Chorioamnionitis: Considerations for Translational Medicine.

Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.

Distinctive Neuroimaging Pattern in Term Newborns With Neonatal Placental Encephalopathy: A Case Series.

BACKGROUND: Identifying antepartum versus intrapartum timing and the cause of neonatal encephalopathy (NE) often remains elusive owing to our limited understanding of the underlying pathophysiological processes and lack of appropriate biomarkers. OBJECTIVES: This retrospective observational study describes a case series of term newborns with NE who displayed a recognizable magnetic resonance imaging pattern of immediately postnatal brain abnormalities that rapidly evolved toward cavitation. Our aim is to (1) report this neuroimaging pattern, (2) look for placental determinants, and (3) depict the outcome. DESIGN/METHODS: This is a unicentric retrospective case series reporting the clinical, radiological, and laboratory findings of NE associated with a distinctive neuroimaging pattern, that is, immediately postnatal extensive corticosubcortical T2 hyperintensities, followed by rapid corticosubcortical cavitation that does not match the neuroimaging picture of intrapartum hypoxic-ischemic encephalopathy (HIE). RESULTS: Seven term newborns presented bilateral corticosubcortical hyperintensities that were detected on T2 between day of life (DOL) 1-4, which rapidly evolved toward cystic encephalomalacia, that is, between DOL9 and DOL12. All these newborns presented with moderate/severe NE. The outcome was either neonatal death or quadriplegic cerebral palsy and epilepsy. None of the reported patients fulfilled the criteria of a high likelihood of acute intrapartum hypoxic-ischemic or quadriplegic cerebral palsy. All these newborns were exposed to chronic and/or acute placental inflammation and/or hypoxic-ischemic. CONCLUSIONS: To further define the antepartum causes of NE, early neuroimaging and a placental examination are recommended. Brain T2 hyperintense injuries before DOL4 followed by rapid cavitation before DOL12 might be biomarkers of NE from an antepartum/placental origin.

Uvaol Prevents Group B Streptococcus-Induced Trophoblast Cells Inflammation and Possible Endothelial Dysfunction.

Group B Streptococcus (GBS) infection during pregnancy is involved in maternal sepsis, chorioamnionitis, prematurity, fetal infection, neonatal sepsis, and neurodevelopmental alterations. The GBS-induced chorioamnionitis leads to a plethora of immune and trophoblast cells alterations that could influence endothelial cells to respond differently to angiogenic mediators and alter placental vascular structure and function in pregnant women. In this context, preventive measures are needed to reduce such dysfunctions. As such, we evaluated the effects of a non-lethal exposure to inactivated GBS on trophoblast cells and chorionic villi explants, and if the treatment with uvaol would mitigate these effects. The concentration of 106 CFU of GBS was chosen since it was unable to reduce the HTR-8/SVneo cell line nor term chorionic villi explant viability. Raman spectroscopy of trophoblast cells showed significant alterations in their biochemical signature, mostly reverted by uvaol. GBS exposure increased HTR-8/SVneo cells IL-1ß and IFN-γ production, phagocytosis, oxidative stress, and decreased trophoblast cell migration. The Ea.hy926 endothelial cell line produced angiopoietin-2, CXCL-8, EGF, FGF-b, IL-6, PlGF, sPECAM-1, and VEGF in culture. When co-cultured in invasion assay with HTR-8/SVneo trophoblast cells, the co-culture had increased production of angiopoietin-2, CXCL-8, FGF-b, and VEGF, while reduced sPECAM-1 and IL-6. GBS exposure led to increased CXCL-8 and IL-6 production, both prevented by uvaol. Chorionic villi explants followed the same patterns of production when exposed to GBS and response to uvaol treatment as well. These findings demonstrate that, even a non-lethal concentration of GBS causes placental inflammation and oxidative stress, reduces trophoblast invasion of endothelial cells, and increases CXCL-8 and IL-6, key factors that participate in vascular dysregulation observed in several diseases. Furthermore, uvaol treatment prevented most of the GBS-provoked changes. Hence, uvaol could prevent the harmful effects of GBS infection for both the mother and the fetus.

Hirayama Disease in a Patient with a History of Late-Onset Symptomatic Vein of Galen Aneurysmal Malformation.

INTRODUCTION: The purpose of this report is to present a rare case of Hirayama disease (HD) in a patient with a history of late-onset symptomatic vein of Galen aneurysmal malformation (VGAM). This report may provide new insights into the pathophysiology of HD, a rare disorder consisting of insidious onset of unilateral weakness and atrophy of the forearm and intrinsic hand muscles. These symptoms are believed to result from cervical myelopathy affecting the anterior horn cells due to abnormal compressive forces on the spinal cord from adjacent anatomical structures (i.e., dura and/or epidural veins), but this has not been proven. VGAM is a rare congenital cerebral vascular malformation, consisting of high-flow arteriovenous shunting between a persistent median prosencephalic vein and arterial feeders, which most frequently presents in the early neonatal period with congestive heart failure. CASE PRESENTATION: We report the case of an otherwise healthy boy who presented with heart failure due to VGAM at 7 years and subsequently presented at 14 years with left-sided HD. His cervical MRI with neck flexion revealed enlarged epidural veins at the C5-C6 spinal level with anterior, leftward displacement of the posterior dura and spinal cord as well as left hemicord flattening and/or atrophy at this level. He underwent successful surgical treatment by C5-C6-C7 osteoplastic laminotomies and tenting and expansile autologous duraplasty, during which enlarged, engorged epidural veins were confirmed and coagulated. This halted the progression of his left hand weakness and atrophy and allowed significant functional improvement. Postoperative catheter angiogram showed no anatomical connection between the persistent VGAM and the engorged epidural veins, and genetic testing revealed no genetic predisposition of vascular malformations. DISCUSSION/CONCLUSION: In this patient, a combined surgical technique was performed that included epidural venous plexus coagulation with posterior autologous duraplasty and dural fixation using tenting sutures. This combined approach led to a favorable clinical and radiographic outcome with no complications or limitations and has not been previously proposed in the literature, to our knowledge. Although not completely ruled out, we found no angiographic connection or genetic predisposition to suggest there is a pathophysiological link between HD and VGAM.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS).

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

Necroptotic neuronal cell death in amyotrophic lateral sclerosis: A relevant hypothesis with potential therapeutic implication?

Necroptosis is emerging among possible mechanisms underlying cell death in neurodegenerative diseases. In this line, we hypothesize that necroptosis might be implicated in neuronal cell death in amyotrophic lateral sclerosis (ALS). To support this hypothesis, we hereby provide pilot data as well as some findings from the literature about the expression of key markers of the necroptotic pathway in ALS. Our preliminary data indicate the upregulation of key markers of necroptosis activation in lower motor neurons of the spinal cord. These human-derived data combined with some clinical and preclinical findings support our hypothesis testing the involvement of necroptosis in lower motor neurons death in ALS patients. These results pave the way to deepen the role of necroptosis in ALS using both preclinical and clinical approaches. If confirmed, this hypothesis might raise new interventional strategies to alleviate neurodegenerative process in ALS.

Cost-effectiveness of fingolimod versus interferon-ß1a for the treatment of pediatric-onset multiple sclerosis in Canada.

AIMS: To evaluate the cost-effectiveness of fingolimod versus interferon (IFN)-ß1a at a dose of 30 µg per week for the treatment of relapsing pediatric-onset multiple sclerosis (POMS) in Canada. MATERIAL AND METHODS: A discrete-time Markov model was developed to compare fingolimod with IFN ß-1a over a time horizon of two years representing patients followed up to mean age of 18 years from a Canadian health care system perspective. Twenty-one health states based on the Expanded Disability Status Scale (EDSS) were considered: EDSS 0‒9 for relapsing multiple sclerosis (MS), EDSS 0‒9 for secondary progressive MS, and "Death." Relative treatment efficacy for fingolimod versus IFN-ß1a was estimated from the PARADIGMS study. Costs and resource use were obtained from published literature and Canadian sources. Utilities were estimated by mapping the Pediatric Quality of Life inventory data onto the Child Health Utility Index-9 Dimension using a published mapping algorithm. Future costs and benefits were discounted at 1.5% per annum. RESULTS: Compared with IFN ß-1a, fingolimod led to an increase in quality-adjusted life-years (QALYs) (0.125) with incremental costs (Canadian dollars [CAD] 2,977) and to an incremental cost-effectiveness ratio (ICER) of CAD 23,886/QALY over a time horizon of two years representing patients followed up to mean age of 18 years. The monetary benefits of fingolimod treatment versus IFN ß-1a at a willingness-to-pay (WTP) threshold of CAD 50,000 per QALY gained were higher than the costs. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) both confirmed the robustness of the results. LIMITATIONS: The main limitations of this analysis primarily stem from the limited data availability in POMS. CONCLUSIONS: Fingolimod is cost effective compared with IFN ß-1a for the treatment of POMS over a time horizon of two years representing patients followed up to a mean age of 18 years in Canada.

Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

BACKGROUND: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. METHODS: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. FINDINGS: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). INTERPRETATION: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. FUNDING: None.

Perinatal inflammation is associated with social and motor impairments in preterm children without severe neonatal brain injury.

OBJECTIVE: To test the association between exposure to perinatal inflammation - i.e. clinical chorioamnionitis or early-onset neonatal infection - in preterm children without severe neonatal brain injury and neurodevelopmental outcome at 30 months of corrected age (CA). DESIGN: Cross-sectional study from a French regional cohort of clinical follow-up (SEVE Network). PATIENTS: One hundred sixty-four surviving neonates without severe brain injury - namely, grade III and IV cerebral hemorrhage and cystic periventricular leukomalacia - and without late-onset neonatal inflammation exposure - namely, late-onset neonatal infection and necrotizing enterocolitis -, born at less than 33 weeks of gestational age from November 2011 to June 2015 and enrolled in the SEVE Network. MAIN OUTCOME MEASURE: Global developmental quotient (DQ) score of the revised Brunet-Lézine scale and its four indices measured by the same neuropsychologist at 30 months of CA. RESULTS: After multivariate analysis, exposure to perinatal inflammation was not found significantly associated with a modification of the global DQ score (coefficient -1.7, 95% CI -4.8 to 1.3; p = 0.26). Exposure to perinatal inflammation was associated with a decrease of the gross motor function DQ score (coefficient -6.0, 95% CI -9.9 to -2.1; p < 0.01) and a decrease of the sociability DQ score (coefficient -5.1, 95% CI -9.2 to -0.9; p = 0.02). Language and visuospatial coordination DQ scores were not affected by exposure to perinatal inflammation. CONCLUSION: Exposure to perinatal inflammation in preterm children without severe neonatal brain injury is independently associated with decreased motor and social abilities at 30 months of CA.

Ampicillin Treatment Increases Placental Interleukin-1 Beta Concentration and Polymorphonuclear Infiltration in Group B Streptococcus-Induced Chorioamnionitis: A Preclinical Study.

BACKGROUND: Antibiotic therapy during preterm labor with intact membranes has been associated with an increased risk of neonatal death. OBJECTIVES: Using an established rat model of group B Streptococcus (GBS)-induced chorioamnionitis, we hypothesized that ampicillin treatment increases placental inflammation, as shown in other bacterial infections. METHODS: At gestational day 19, 19 Lewis dams were intraperitoneally (i.p.) inoculated by 108 CFU of ß-hemolytic serotype Ia GBS (strain #16955 susceptible to ampicillin). Dams were treated i.p. with either 200 mg/kg of ampicillin (n = 9) or 0.9% saline (n = 10) at 48 and 60 h post-GBS inoculation. Cesarean sections were performed 72 h post-GBS inoculation. RESULTS: Ampicillin treatment was associated with an increased number of polymorphonuclear cells (PMN) infiltrating the decidua (mean 1,536 vs. 532 PMN/mm2; p < 0.001) and a higher placental concentration of IL-1ß (mean 26.4 vs. 7.9 pg/mg; p < 0.01) compared to saline-treated dams. These effects were observed in dams without GBS bacteremia. Conversely, ampicillin treatment was associated with a decreased placental concentration of proinflammatory cytokines in dams with GBS bacteremia. CONCLUSIONS: Ampicillin increases placental inflammation in a rat model of GBS-induced chorioamnionitis without bacteremia. This proinflammatory effect of ampicillin could be due to bacterial lysis. Our findings do not query the intrapartum antibiotic prophylaxis against GBS disease. They pave the way for future preclinical studies combining anti-inflammatory treatments and antibiotic therapy for GBS-induced chorioamnionitis.