Pneumococcal pneumonia and endotoxemia: An experimental and clinical reappraisal.

BACKGROUND: Circulating endotoxins could result from bacterial digestive translocation during sepsis, thus contributing to uncontrolled systemic inflammation, leading in turn to organ dysfunction. We addressed this issue in the setting of severe pneumococcal pneumonia. METHODS: Endotoxemia was measured in a clinically relevant rabbit model of ventilated pneumococcal pneumonia and in 110 patients with bacteraemic pneumonia, using a patented mass spectrometry (LC-MS/MS) method for detection of 3-OH fatty acids (C10, C12, C14, C16 and C18), which are molecules bound to the lipid A motif of LPS. RESULTS: Whereas higher levels of systemic inflammation and organ dysfunctions were found, there was no significant difference in lipopolysaccharide concentrations when infected rabbits were compared to non-infected ones, or when patients were compared to healthy volunteers. CONCLUSIONS: Seemingly, endotoxins do not drive the overwhelming inflammation associated with severe forms of pneumococcal pneumonia.

Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected.

The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b-/- mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.

Use of EEG in neonatal hypoxic-ischemic encephalopathy: A French survey of current practice and perspective for improving health care.

OBJECTIVES: Controlled therapeutic hypothermia (CTH) is a standard of care in the management of neonatal hypoxic-ischemic encephalopathy HIE in newborns after 36 weeks of gestational age (WGA) in France. The electroencephalogram (EEG) plays a major role in HIE diagnosis and follow-up. We conducted a French national survey on the current use of EEG in newborn undergoing CTH. METHODS: Between July and October 2021, an email survey was sent to the heads of the Neonatal intensive care units (NICUs) in metropolitan and overseas French departments and territories. RESULTS: Out of 67, 56 (83%) of NICUs responded. All of them performed CTH in children born after 36 WGA with clinical and biological criteria of moderate to severe HIE. 82% of the NICUs used conventional EEG (cEEG) before 6 h of life (H6), prior to CTH being performed, to inform decisions about its use. However, half of the 56 NICUs had limited access after regular working hours. 51 of the 56 centers (91%) used cEEG, either short-lasting or continuous monitoring during cooling, while 5 centers conducted only amplitude EEG (aEEG). Only 4 of 56 centers (7%) used cEEG systematically both prior to CTH and for continuous monitoring under CTH. DISCUSSION: The use of cEEG in the management of neonatal HIE was widespread in NICUs, but with significant disparities when considering 24-hour access. The introduction of a centralized neurophysiological on-call system grouping several NICUs would be of major interest for most centers which do not have the facility of EEG outside working hours.

Quantitative Neuroanatomical Phenotyping of the Embryonic Mouse Brain.

Congenital neurodevelopmental anomalies are present from birth and are characterized by an abnormal development of one or more structures of the brain. Brain structural anomalies are highly comorbid with neurodevelopmental and neuropsychiatric disorders such as intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia, and 80% are of genetic origin. We aim to address an important neurobiological question: How many genes regulate the normal anatomy of the brain during development. To do so, we developed a quantitative approach for the assessment of a total of 106 neuroanatomical parameters in mouse mutant embryos at embryonic day 18.5 across two planes commonly used in brain anatomical studies, the coronal and sagittal planes. In this article we describe the techniques we developed and explain why ultrastandardized procedures involving embryonic mouse brains are even more of prime importance for morphological phenotyping than adult mouse brains. We focus our analysis on brain size anomalies and on the most frequently altered brain regions including the cortex, corpus callosum, hippocampus, ventricles, caudate putamen, and cerebellum. Our protocols allow a standardized histology pipeline from embryonic mouse brain preparation to sectioning, staining, and scanning and neuroanatomical analyses at well-defined positions on the coronal and sagittal planes. Together, our protocols will help scientists in deciphering congenital neurodevelopmental anomalies and anatomical changes between groups of mouse embryos in health and genetic diseases. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Fixation and preparation of embryonic mouse brain samples Basic Protocol 2: Sectioning, staining, and scanning of embryonic mouse brain sections Basic Protocol 3: Coronal neuroanatomical measurements of embryonic mouse brain structures Basic Protocol 4: Sagittal neuroanatomical measurements of embryonic mouse brain structures.

Associations between fetal heart rate variability and umbilical cord occlusions-induced neural injury: An experimental study in a fetal sheep model.

INTRODUCTION: This study evaluated the association between fetal heart rate variability (HRV) and the occurrence of hypoxic-ischemic encephalopathy in a fetal sheep model. MATERIAL AND METHODS: The experimental protocol created a hypoxic condition with repeated cord occlusions in three phases (A, B, C) to achieve acidosis to pH <7.00. Hemodynamic, gasometric and HRV parameters were analyzed during the protocol, and the fetal brain, brainstem and spinal cord were assessed histopathologically 48 h later. Associations between the various parameters and neural injury were compared between phases A, B and C using Spearman's rho test. RESULTS: Acute anoxic-ischemic brain lesions in all regions was present in 7/9 fetuses, and specific neural injury was observed in 3/9 fetuses. The number of brainstem lesions correlated significantly and inversely with the HRV fetal stress index (r = -0.784; p = 0.021) in phase C and with HRV long-term variability (r = -0.677; p = 0.045) and short-term variability (r = -0.837; p = 0.005) in phase B. The number of neurological lesions did not correlate significantly with other markers of HRV. CONCLUSIONS: Neural injury caused by severe hypoxia was associated with HRV changes; in particular, brainstem damage was associated with changes in fetal-specific HRV markers.

Factors impacting performance on the 6-minute walk test by people with late-onset Pompe disease.

INTRODUCTION/AIMS: Pompe disease is a progressive myopathy that combines motor, respiratory, and cardiac impairments. The 6-min walk test is the gold standard for assessing disease severity at the motor level. The objective of this study was to better determine the parameters that influence the total distance covered in patients with Pompe disease. METHODS: We performed a retrospective review of 15 patients with late-onset Pompe disease who were followed regularly at a single referral center. Logistic regression was used to investigate the links between motor, respiratory and cardiac variables and 6-min walk test performance. RESULTS: When considering baseline clinical and demographic variables, a seven-step backward elimination regression analysis yielded a model with two predictors (age and the use of an assistive device) that explained 85.5% of the variance. When considering the cardiorespiratory variables monitored during gait, a three-step backward elimination regression analysis showed that two predictors (heart rate recovery and the baseline partial pressure of carbon dioxide) explained 42.2% of the variance. DISCUSSION: Our results highlighted the importance of respiratory and cardiac adaptation during exercise (along with motor ability) during the 6-min walk test in patients with Pompe disease. Further studies of larger cohorts are necessary to validate the model, which might enable investigators to determine whether intra-individual fluctuations in 6-min walk test performance are related to physiological parameters and/or to other variables such as the patient's level of motivation during the test.

Modalities and Determinants of Career Paths in Pediatrics: A Survey of Former Pediatric Residents From Lille University Medical Center.

There is currently a shortage of pediatricians in the Nord-Pas-de-Calais (NPC) area of France. The shortage affects both hospital positions (since many departures are not replaced) and private practice. The objectives of the present study were to (i) describe the career paths of former pediatric residents from Lille University Medical Center, (ii) identify factors associated with leaving NPC and leaving hospital-based practice, and (iii) compare the characteristics associated with the various types of practice. Methods: Pediatric residents having started their residency at Lille University Medical Center between 1993 and 2013 were invited to fill out an online questionnaire. Main outcomes were leaving NPC and leaving hospital practice. The event rate at different times over a 10-year period was determined using the Kaplan-Meier method. Results: The response rate was 92% (284 out of 310 invited respondents): 61% had changed their place or type of practice at least once, 54% had moved to a different city, and 41% had left NPC. Having trained elsewhere than in Lille and the lack of a chief assistant specialist position in NPC were independently associated with leaving NPC. 73% of the respondents were currently in hospital-based practice. Having started residency after 2003, taking a sabbatical during the residency and not training in a subspecialty (other than general pediatrics) were independently associated with leaving hospital-based practice. The stated reasons for leaving hospital-based practice were on-call duties (according to 71% of the respondents), overwork (46%), family reasons (34%), and a poor atmosphere at work (34%). Hospital-based pediatricians were more active in research and teaching. They worked an average of 13 h more per week than the other respondents, and were less satisfied with their choice of professional activity and their work-life balance. Conclusion: Changes in the place or type of practice have become frequent. With the recent resurgence of interest in private practice, leaving hospital is reportedly associated with better working conditions, greater satisfaction, and a better work-life balance.

Three cases of adult-onset Brown-Vialetto-Van Laere syndrome: Novel variants in SLC52A3 gene and MRI abnormalities.

Brown-Vialetto-Van Laere syndrome is a rare, autosomal, recessive neurological condition caused by variants in the riboflavin transporter genes SLC52A2 and SLC52A3. Here, we report on three cases. Case 1 was a 35-year-old woman from a consanguineous family who presented with progressive deafness, subacute multiple cranial nerve impairments (III, VII, IX, XII), and MRI abnormalities (including as hypersignal from the cranial nerves). The patient was homozygous for a novel SLC52A3variant. Case 2 was the woman's brother, who presented similar symptoms. Case 3 was an 18-year-old woman experiencing progressive hearing loss, bilateral steppage gait and a cranial nerves impairment (VII and XII). MRI revealed hypersignal in the root nerves and cauda equina. A novel heterozygous variant in SLC52A3 was identified. A subacute history of polyradiculoneuropathy along with progressive deafness, cranial nerve impairment, and MRI abnormalities should raise suspicion for Brown-Vialetto-Van Laere syndrome.

Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.

PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized. METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. RESULTS: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. CONCLUSION: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors.

Purpose: Cohen syndrome (CS) is a rare genetic disorder caused by variants of the VPS13B gene. CS patients are affected with a severe form of retinal dystrophy, and in several cases cataracts also develop. The purpose of this study was to investigate the mechanisms and risk factors for cataract in CS, as well as to report on cataract surgeries in CS patients. Methods: To understand how VPS13B is associated with visual impairments in CS, we generated the Vps13b∆Ex3/∆Ex3 mouse model. Mice from 1 to 3 months of age were followed by ophthalmoscopy and slit-lamp examinations. Phenotypes were investigated by histology, immunohistochemistry, and western blot. Literature analysis was performed to determine specific characteristic features of cataract in CS and to identify potential genotype-phenotype correlations. Results: Cataracts rapidly developed in 2-month-old knockout mice and were present in almost all lenses at 3 months. Eye fundi appeared normal until cataract development. Lens immunostaining revealed that cataract formation was associated with the appearance of large vacuoles in the cortical area, epithelial-mesenchymal transition, and fibrosis. In later stages, cataracts became hypermature, leading to profound retinal remodeling due to inflammatory events. Literature analysis showed that CS-related cataracts display specific features compared to other forms of retinitis pigmentosa-related cataracts, and their onset is modified by additional genetic factors. Corroboratively, we were able to isolate a subline of the Vps13b∆Ex3/∆Ex3 model with delayed cataract onset. Conclusions: VPS13B participates in lens homeostasis, and the CS-related cataract development dynamic is linked to additional genetic factors.

Fetal sheep cerebral electrical activity: A new technique to record EEG.

BACKGROUND: Sheep models are commonly used to study fetal cortical activity, including response to hypoxia. The standard technique consists of recording electrocorticogram (ECOG) in utero using electrodes placed on the dura mater. NEW METHOD: We propose a new method for recording the electroencephalogram (EEG) of fetal sheep, using electrodes placed above the skull bone and fixed to the cranial periosteum. RESULTS: Twelve animals were instrumented with this new technique. The EEG signal recorded in utero was of sufficient quality for visual and quantitative analysis of the fetal cortical activity. COMPARISON WITH EXISTING METHOD: This new method is less invasive than the standard method commonly used to record cerebral activity in fetal sheep, because it avoids drilling the skull by hand. The EEG signal recorded in utero had visual and quantitative characteristics comparable to ECOG. CONCLUSIONS: We present a new method of EEG recording that appears to be an acceptable alternative to the standard ECOG recording method. Fetal sheep EEG can be used to better understand the physiological mechanisms involved in the cerebral response to hypoxia.

Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.

N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.

Relationship between somatosensory deficit and brain somatosensory system after early brain lesion: A morphometric study.

Cerebral Palsy (CP) is a group of permanent motor disorders due to non-progressive damage to the developing brain. Poor tactile discrimination is common in children with unilateral CP. Previous findings suggest the crucial role of structural integrity of the primary (S1) and secondary (S2) somatosensory areas located in the ipsilesional hemisphere for somatosensory function processing. However, no focus on the relationship between structural characteristics of ipsilesional S1 and S2 and tactile discrimination function in paretic hands has been proposed. Using structural MRI and a two-point discrimination assessment (2 PD), we explore this potential link in a group of 21 children (mean age 13 years and 7 months) with unilateral CP secondary to a periventricular white matter injury (PWMI) or middle cerebral artery infarct (MCA). For our whole sample there was a significant negative correlation between the 2 PD and the gray matter volume in the ipsilesional S2 (rho = -0.50 95% confidence interval [-0.76, -0.08], one-tailed p-value = 0.0109) and in the ipsilesional S1 (rho = -0.57, 95% confidence interval [-0.81, -0.19], one-tailed p-value = 0.0032). When studying these relationships with regard to the lesion types, we found these correlations were non-significant in the patients with PWMI but stronger in patients with MCA. According to our results, the degree of sensory impairment is related to the spared gray matter volume in ipsilesional S1 and S2 and is marked after an MCA stroke. Our work contributes to a better understanding of why some patients with CP have variable somatosensory deficit following an early brain lesion.

Dermatologic features of Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is characterized by distinctive facial and skeletal features, developmental delay, cognitive impairment, and behavioral abnormalities, including self-injurious behaviors. We aimed to investigate whether cutaneous features are common in SMS. We performed a complete skin examination in 20 young SMS patients. Skin features secondary to self-injurious behavior, such as bites, abrasions, dystrophic scars, limited spots of hyperkeratosis, anomalies of the nails, and whitlows, were found in the majority of patients. Acral pachydermia and fissured plantar keratoderma were common. Xerosis was constant and associated with extensive keratosis pilaris in the majority of patients. Dermatofibromas were frequent in older patients. The hair was dense and shiny, with an unusual hairline. Eyelash trichomegaly and heavy brows were common, as well as folliculitis on the back. The skin features of SMS have rarely been reported in the literature. Some of these are the consequence of neurobehavioral features, but some cutaneous features and abnormalities of appendages have not been reported in other related syndromes. Skin manifestations of SMS are varied, sometimes induced by self-injurious behavior and sometimes more specific. It remains to be determined whether the combination of the two kinds of signs could contribute to early diagnosis of the syndrome.

Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.

OBJECTIVE: The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs). METHODS: Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA. RESULTS: All patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation. INTERPRETATION: Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a "2-hit" mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable.

A new virtual reality tool for unilateral cerebral palsy rehabilitation: two single-case studies.

OBJECTIVE: To examine the "clinical utility" of a new virtual rehabilitation tool in order to treat upper-limb motor deficit in cerebral palsy (CP) patient. METHODS: Single-case experimental designs. Virtual reality intervention was performed in two left unilateral spastic CP adolescent patients. The virtual reality intervention was given for 60 minutes per session, two sessions a day, and 5 days a week over 2 weeks. RESULTS: For each patient and for both hands, the number of blocks transported within one minute (box and block test scores) is increased. The nonoverlap of all pairs indices for the paretic hand were calculated as 0.95 for subject 1 and 0.93 for subject 2, and the nonoverlap of all pairs indices for the nonparetic hand were calculated, respectively, as 0.92 and 1. CONCLUSION: We provide empirical evidence in support of a new simple Virtual Rehabilitation system in CP patient to improve upper-limb motor function.

Severe bronchiolitis in infants born very preterm and neurodevelopmental outcome at 2 years.

Preterm infants are at greater risk of bronchopulmonary dysplasia, which is associated with neurodevelopmental impairment. These infants are also more likely to develop severe bronchiolitis, which can contribute to neurodevelopmental impairment. The aim of this study was to determine whether severe bronchiolitis in very preterm infants (born before 33 weeks of gestation) was associated with an increased risk of neurodevelopmental impairment at 2 years of age. We analyzed a population-based cohort of infants (the Loire Infant Follow-up Team cohort) born between 1 January 2003 and 31 December 2009. Severe bronchiolitis was defined as hospitalization due to bronchiolitis during the first year of life. Neurodevelopmental outcome was assessed at 2 years of corrected age. A total of 2,405 infants were included in this analysis and categorized based on neonatal respiratory status: 1,308 (54.4 %) received no respiratory assistance, 864(35.9 %) received oxygen for <28 days, and 167 (6.9 %) had mild and 66 (2.7) moderate or severe bronchopulmonary dysplasia. At 2 years, 502 children displayed non-optimal neurodevelopmental outcome (20.9 %). Moderate or severe bronchopulmonary dysplasia was significantly associated with non-optimal neurodevelopmental outcome at 2 years (adjusted odds ratios (OR) = 2.3 [95 % confidence interval (CI): 1.3-3.9], p = 0.003). In the first year, 318 infants acquired severe bronchiolitis (13.2 %), which was not associated with non-optimal neurodevelopmental outcome (adjusted OR = 1.0 [95 % CI: 0.8-1.4]; p = 0.88). In conclusion, respiratory status in the neonatal period was significantly associated with non-optimal neurodevelopmental outcome at 2 years, while severe bronchiolitis was not.