Marjo Metsäranta

Early acquired brain injury is a major risk factor for infantile epileptic spasms syndrome (IESS), which may impair cognitive development, especially if diagnosis and treatment are delayed. However, individual-level prediction of which infants will develop IESS is currently not possible. We assessed whether high-frequency oscillations (HFOs) in scalp EEG or recurrent interictal epileptiform discharges (IED) during the first months of life could predict forthcoming IESS. Our population-based cohort included 36 infants with cortical injury due to infarction, haemorrhage, infection or trauma involving a large cortical area (≥ anterior/posterior cerebral artery territory or ≥ half of the middle cerebral artery territory), or hypoxic-ischaemic encephalopathy with cortical and deep grey matter involvement. The infants underwent repeated EEGs during the first year of life until 12 months of age or until IESS diagnosis. HFOs during sleep were scored both visually and automatically, whereas IEDs were assessed visually only. We tested whether HFO rate increased during the first year of life using a mixed-effects model with within- and between-subject random effects. Using only EEGs recorded prior to IESS diagnosis, we evaluated whether HFO rate or recurrent IEDs could predict IESS development by training a ridge-regularized logistic regression model with exhaustive leave-2-subjects-out cross-validation. Eleven infants (31%) developed IESS. HFO rate increased with age in both groups but more steeply in the IESS group [within person slope β = 2.43 (IESS) vs. 0.06 (no-IESS) units/month, P < 0.001]. The logistic regression model showed that both HFO rate [AUC 0.801 (95% CI 0.668, 0.936)] and recurrent IEDs [AUC 0.826 (95% CI 0.720, 0.932)] were able to predict forthcoming IESS. However, in a multivariable model, only recurrent IEDs remained independently associated with IESS, and HFO rate did not add predictive value. The marked increase in HFO rate toward IESS diagnosis supports their role as a biomarker of epileptogenesis. During the first months of life, HFOs and recurrent IEDs performed equally well in predicting subsequent IESS. However, IEDs are easier to apply to clinical practice.

Background Prediction of long-term neurodevelopmental outcomes remains challenging after perinatal asphyxia. Here, we studied whether computational metrics of brain function derived from neonatal EEG are associated with long-term neurodevelopment in infants with perinatal asphyxia. Methods Total of 36 term-born infants with perinatal asphyxia with or without hypoxic-ischemic encephalopathy were studied with neonatal multichannel electroencephalography (EEG). We computed local EEG amplitudes and phase-amplitude coupling (PAC), as well as large-scale functional cortical networks estimated using amplitude-amplitude correlations (AAC) and phase-phase correlations (PPC). These EEG-derived markers were tested for associations with neurodevelopmental outcomes at two years, assessed using the Griffiths Scales of Child Development, 3rd edition (GMDS-III). Results EEG amplitudes showed positive associations with GMDS-III Foundations of Learning and General Development scores across most electrodes during quiet sleep, with the strongest effects observed at frontal and central regions (r = 0.44-0.66). PAC showed negative associations with the same scores mainly over parietal and temporal regions (r = -0.45 to -0.55). Cortical AAC networks demonstrated the most robust and widespread negative associations in all frequency bands during quiet sleep (r = -0.47 to -0.54), with 70-72% of connections significant in high delta frequency. In turn, PPC networks showed frequency-selective and more spatially constrained negative associations during quiet sleep (r = -0.48 to -0.53), involving 5-12% of the network. Conclusions Both local and network-based metrics in the newborn brain show significant association with neurodevelopmental outcome at 2 years after perinatal asphyxia.

The aims of this prospective study were to describe feeding difficulties in term infants with perinatal asphyxia and to determine whether the time it takes to achieve full oral feeding correlates with early neurological outcome in a high-income setting. Recruitment included 52 term infants with perinatal asphyxia: 32 without hypoxic-ischaemic encephalopathy (HIE), 9 with mild HIE, and 11 with moderate HIE. The time in days it takes to achieve full oral independent feeding was used as a marker of feeding difficulty. Early neurological outcome was evaluated using neonatal brain magnetic resonance imaging (MRI) and Hammersmith Infant Neurological Examination (HINE) at 3 months. In this cohort, 85% of infants (44/52) needed short-term assisted feeding after birth. The time it takes to achieve full oral feeding correlated with neonatal brain MRI findings and structured neurological examination results at three months. The time it takes to achieve full oral feeding could be a useful clinical measure to assess neurologic recovery after perinatal asphyxia, especially in low-resource settings.

Aim: We aimed to describe clinical practices and criteria for discharge of very preterm infants in Nordic neonatal units.Methods: Medical directors of all 89 level‐2 and level‐3 units in Denmark, Finland, Iceland, Norway and Sweden were invited by e‐mail to complete a web‐based multiple‐choice survey with the option to make additional free‐text comments.Results: We received responses from 83/89 units (93%). In all responding units, discharge readiness was based mainly on clinical assessment with varying criteria. In addition, 36% used formal tests of cardiorespiratory stability and 59% used criteria related to infant weight or growth. For discharge with feeding tube, parental ability to speak the national language or English was mandatory in 45% of units, with large variation among countries. Post‐discharge home visits and video‐consultations were provided by 59% and 51%, respectively. In 54% of units, parental preparation for discharge were not initiated until the last two weeks of hospital stay.Conclusion: Discharge readiness was based mainly on clinical assessment, with criteria varying among units despite similar population characteristics and care structures. This variation indicates a lack of evidence base and may unnecessarily delay discharge; further studies of this matter are needed. Earlier parental preparation and use of interpreters might facilitate earlier discharge.

Aim: To characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia.Methods: The prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016–2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age.Results: Analysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic‐ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity.Conclusion: In this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE.

Cartilage collagens type II and type IX exist in two alternative forms which arise from alternative splicing and alternative use of promoters, respectively. In the present study we analyzed temporal and spatial expression patterns of the two isoforms of type II and type IX collagen transcripts as well as those of α2(IX) and α3(IX) collagen mRNAs in limb cartilages and eyes during mouse embryonic development. Northern and RNase protection assays revealed temporal coregulation of the two alternative isoforms in limbs, but not in the eye where no long form of α1(IX) collagen mRNA was detected. Although in situ hybridization of limbs revealed identical expression patterns of the long form of type II collagen and the short form of α1(IX) collagen mRNA in the perichondrium and periosteum of 14.5–18.5-day embryos, the patterns were distinctly different at day 12.5 of development: the long form of type II collagen mRNA was expressed throughout the developing cartilaginous anlage whereas the short form of α1(IX) collagen mRNA was expressed in the surrounding mesenchyme. Some differences were also detected in the temporal and spatial expression patterns between the α1(IX), α2(IX), and α3(IX) collagen mRNAs. In the eyes, α2(IX) collagen mRNA had highest expression levels at day 12.5, whereas α1(IX) and α3(IX) collagen mRNAs peaked later, at day 16.5. In the limbs, α1(IX) and α3(IX), but not α2(IX), collagen mRNAs were detected in periosteal cells after 16.5 days of development. In transgenic Del1 mice, harboring type II collagen transgenes with a small deletion mutation, expression of mutant mRNA affected neither the alternative splicing of wild-type or mutant transcripts nor the ratio of the two alternative forms of the α1(IX) collagen mRNA. Despite some distinct similarities, the two alternative forms of type II and type IX collagen must, therefore, be under differential control during mouse development.

Several techniques were used to study the co-ordination of mRNA levels for five constituent chains of cartilage collagen fibrils during mouse development. Short cDNA clones were first constructed for mouse and human α3(IX) and for mouse proα1(XI) collagen mRNA species. Northern analysis of developing mouse embryos revealed that the mRNA species for α1, α2 and α3 chains of type IX collagen peaked earlier than those for proα1(II) and proα1(XI) collagen chains. Quantification of these mRNA species by slot-blot hybridization confirmed this developmental regulation: the mRNA ratios for type II/type IX/type XI collagens changed from 5.7:1:0.6 (at embryonic day 12.5) to 10.6:1:0.9 (in newborn mice). However, the genes coding for the three chains of type IX collagen seemed to be under more co-ordinated regulation during mouse development. In addition to high mRNA levels in cartilages and the eye, low levels of type IX collagen transcripts were identified in brain and skin of newborn mouse using RNase protection and reverse transcriptase–PCR assays. Finally, hybridization in situ revealed identical tissue distributions of the three type IX collagen mRNA species during early chondrogenesis but somewhat more widespread expression of the α1(IX) and α3(IX) mRNA species during endochondral ossification at day 16.5 of embryonic development. These results suggest a relatively tight co-ordination of the α1(IX), α2(IX), and α3(IX) collagen mRNA species in chondrocytes, but a lack of co-ordination in several non-cartilaginous tissues.