Risonanza magnetica cerebrale e outcome neurologico nei pazienti con peso molto basso alla nascita: ruolo delle alterazioni di sostanza bianca e delle altre lesioni cerebrali connesse con la prematurit\ue0

Introduzione e Scopo dello Studio. Negli ultimi decenni il miglioramento delle cure perinatali e l\u2019aumento della sopravvivenza dei nati pretermine di peso molto basso alla nascita (< 1500g, Very Low Birth Weight, VLBW) \ue8 stato accompagnato da una drastica riduzione delle lesioni cerebrali gravi, come la leucomalacia periventricolare (PVL). Nel contempo un pi\uf9 diffuso uso della risonanza magnetica ha permesso di identificare lesioni sempre pi\uf9 lievi, con significato prognostico incerto, come lesioni puntate della sostanza bianca (Punctate White Matter Lesions, PWML). Recentemente sono stati evidenziati due sottotipi di PWML: di tipo emorragico (visibili alla sequenza SWI) e non-emorragico (negative alla SWI e visibili nelle sole sequenze T1 e T2). Un primo scopo dello studio \ue8 stato quello di evidenziare i fattori di rischio clinici e il significato prognostico in termini di follow-up psicomotorio di entrambi i sottotipi di PWML. Secondariamente, si \ue8 voluto definire la tipologia e la frequenza delle lesioni di sostanza bianca in confronto alle altre lesioni cerebrali tipiche della prematurit\ue0 evidenziando eventuali differenze nell\u2019outcome neurologico a tre anni di vita. Metodi. Per la prima parte dello studio sono stati inclusi tutti i pazienti VLBW ricoverati presso la U.O. Terapia Intensiva e Patologia Neonatale dell\u2019Istituto G. Gaslini di Genova da gennaio 2012 ad agosto 2016 sottoposti ad RM cerebrale all\u2019et\ue0 corretta del termine; nella seconda parte dello studio la popolazione era ampliata aggiungendo pazienti ricoverati fino a settembre 2017. Per ogni paziente sono stati raccolti dati clinici dettagliati e valori di scala Griffiths a 2 e 3 anni di et\ue0 corretta. Le PWML, definite come lesioni puntiformi della sostanza bianca periventricolare iperintense in sequenza T1 e/o ipointense in sequenza T2, sono stati suddivise in SWI+ PWML e SWI- PWML in base alla visibilit\ue0 in SWI. Le lesioni sono state inoltre classificate in base al numero di lesioni per singolo paziente, alla distanza di lesioni dal ventricolo laterale, alla loro posizione ed alle caratteristiche morfologiche (lineari, a grappolo o singole). \uc8 stata eseguita una analisi multivariata dei fattori di rischio clinici per diverse tipologie delle PWML, inoltre le SWI+ PWML e SWI- PWML sono state confrontate in base alla sede anatomica e al significato prognostico a 2 anni. Nella seconda parte dello studio abbiamo caratterizzato le lesioni cerebrali tipiche della prematurit\ue0 - lesioni di sostanza bianca, emorragia intraventricolare da sanguinamento della matrice germinativa (GMH-IVH), ed emorragia cerebellare (CBH) - in funzione di gravit\ue0, con gli score da 1 a 3. Abbiamo successivamente confrontato l\u2019incidenza di diverse tipologie di lesioni. Sono stati eseguite le misurazioni di parametri lineari caratterizzanti dimensioni cerebrali, come diametro biparietale (BPW) e diametro trans-cerebellare (TCD). \uc8 stato eseguito confronto di valori di Griffiths a 3 anni di et\ue0 tra pazienti con diversi tipologie e gradi di lesioni e pazienti senza lesioni cerebrali; sono state inoltre esplorate possibili correlazioni tra le misure cerebrali e l\u2019outcome. Risultati. Nella prima parte dello studio, le PWML si sono registrate nel 19% (61/321) dei neonati VLBW, dei quali solo il 25% (15/61) presentavano lesioni visibili nella sequenza SWI (SWI+). Le lesioni puntate sono risultate pi\uf9 frequenti nei nati con et\ue0 gestazionale > 28 settimane. Sono risultati fattori di rischio significativi per lo sviluppo delle PWML la profilassi steroidea incompleta (p<0,05) e un peso maggiore alla nascita (p<0,05). Erano pi\uf9 a rischio di sviluppare PWML multiple (pi\uf9 di 6) pazienti che hanno subito l\u2019intubazione (p<0,05) e che avevano un punteggio di Apgar pi\uf9 alto alla nascita (p<0,05). Le SWI+ PWML sono stati associate con la presenza di GMH-IVH (p=0,001) e con et\ue0 gestazionale alla nascita pi\uf9 bassa, inoltre queste lesioni sono risultate pi\uf9 vicino al ventricolo laterale rispetto alle puntate non emorragiche (p<0,001). Al follow-up a 2 anni di et\ue0, pazienti con SWI+ PWML isolate presentavano la riduzione di quoziente di sviluppo su scala D (coordinazione occhio-mano e motricit\ue0 fine) rispetto ai pazienti con imaging normale. Dalla analisi dei dati nella seconda parte dello studio \ue8 emerso che 187 su 408 pazienti (46% di tutti i VLBW) presentavano almeno una lesione cerebrale alla risonanza magnetica, mentre 37 su 408 (9%) presentavano lesioni gravi (grado 3). La lesione pi\uf9 frequente era la emorragia intraventricolare da sanguinamento della matrice germinativa (28% della popolazione), seguita da lesioni della sostanza bianca (PWML e PVL, 21%) ed infine dall\u2019emorragia cerebellare (17%). Presenza di lesioni cerebrali, anche di grado 1, comportava diminuzione significativa dei valori medi della scala di Griffith rispetto ai pazienti che non hanno presentato alcuna lesione cerebrale. Inoltre, abbiamo osservato differenze significative nell\u2019outcome locomotorio (scala A di Griffiths) in modo progressivo tra i pazienti con tre livelli di lesioni della sostanza bianca, da PWML di grado 1 a PVL cistica. Per quanto riguarda le misure lineari, \ue8 stata osservata la correlazione positiva tra valori di Griffiths totale a 3 anni e BPW (r=0.18, p=0.0057), cos\uec come TCD (r=0.27, p<0.001), anche se le correlazioni non erano pi\uf9 statisticamente significativi se si escludevano i pazienti con lesioni. Conclusioni. Abbiamo osservato che le lesioni puntate di natura emorragica (SWI+ PWML) hanno fattori di rischio, posizione anatomica e significato pronostico diversi da quelli non-emorragiche, e che la loro presenza \ue8 collegata alle et\ue0 gestazionali pi\uf9 basse, come succede anche per altre emorragie (GMH-IVH e CBH). Potrebbe quindi essere utile utilizzare questa distinzione anche in ambito clinico. Abbiamo inoltre osservato che anche per lesioni di basso grado (sia per le emorragie che per le lesioni della sostanza bianca) esiste una correlazione negativa con outcome a 3 anni di vita, il fatto che sottolinea l\u2019importanza di diagnostica specifica e valorizza la ricerca in ambito di prevenzione di tali lesioni.Introduction and aims: During last decades better perinatal care and higher survival rates for very low birth weight (<1500 gr, VLBW) infants went hand by hand with an important reduction of incidence of severe brain lesions, as periventricular leukomalacia (PVL). At the same time more widespread use of brain MRI allowed to identify milder lesions, with unknown prognosis, as punctate white matter lesions (PWML). Recently two types of PWML were described: the hemorrhagic ones (visible on SWI sequence) and the non-hemorrhagic ones (negative on SWI and visible only on T1 and T2 sequences). The first aim of this study was to describe clinical risk factors and prognostic significance of both types of PWML. The second aim was to define the type and frequency of white matter lesions when compared to other prematurity-related brain lesions, describing their influence on neurological follow-up at 3 years of age. Methods: In the first part of the work we included all VLBW patients admitted to G. Gaslini Hospital NICU from January 2012 to August 2016 that have performed brain MRI at term-equivalent age; in the second part of the work we added to the population the patients admitted up to September 2017. For each patient we registered detailed clinical data and Griffiths Scale results at 2 and 3 years of age. The PWML, defined as small alterations of signal (high T1 and/or low T2) in the periventricular white matter were divided into SWI+ PWML and SWI- PWML based on their visibility on SWI sequence. The lesions were further classified based on their number, distance from the lateral ventricle, their position and morphological characteristics (linear, cluster or single). Multivariate analysis of risk factors for different types of PWML was carried out; SWI+ PWML e SWI- PWML were compared based on their anatomical characteristics and prognostic meaning at 2 years of age. In the second part of the work we have divided prematurity-related brain lesions - white matter lesions, germinal matrix hemorrhage \u2013 intraventricular hemorrhage (GMH-IVH) and cerebellar hemorrhage (CBH) \u2013 into three grades, with scores from 1 to 3. We have then analyzed the frequency of different types of lesions in our population. We have carried out linear measurements characterizing brain size, such as biparietal width (BPW) and trans-cerebellar diameter (TCD). Values of Developmental Coefficient on Griffiths Scale at 3 years of age were compared between patients with different types and grades of lesions and patients without brain lesions; we have also explored possible correlations between linear brain measurements and outcome. Results: In the first part of the study, PWML were registered in 19% (61/321) of VLBW infants, while only 25% of them (15/61) had lesions visible on SWI (SWI+). PWML were more frequent in patients with gestational age at birth below 28 weeks. Significant risk factors for PWML were absent or incomplete antenatal steroid treatment (p<0,05) and higher birth weight (p<0,05). Patients more at risk of developing multiple (more than 6) PWML were the ones intubated (p<0,05) and with higher Apgar score at birth (p<0,05). SWI+ PWML were associated with the presence of GMH-IVH (p=0,001) and lower gestational age at birth; these lesions were also closer to the lateral ventricle when compared to non-hemorrhagic punctate lesions (p<0,001). At 2 years of corrected age, patients with isolated SWI+ PWML had lower Developmental Coefficient on scale D (eye-hand coordination and fine motricity) when compared to the patients with normal imaging. The second part of the study showed that 187 out of 408 patients (46% of all VLBW) had at least one prematurity-related brain lesion on MRI, while 37 out of 408 (9%) had severe lesions (grade 3). The most frequent lesion was GMH-IVH (28% of the population), followed by white matter lesions (PWML e PVL, 21%) and CBH (17%). The presence of brain lesions, even if of grade 1, was related to a significant reduction of Developmental Coefficient on Griffiths Scale at 3 years of age when compared to infants without lesions. We have further observed significant differences in motor outcome (scale A of Griffiths) distributed progressively among patients with three grades of white matter lesions, from PWML of grade 1 to cystic PVL. We have observed positive correlation between values of Developmental Coefficient on Griffiths Scale at 3 years of age and BPW (r=0.18, p=0.0057), as well as TCD (r=0.27, p<0.001), even if excluding the patients with the brain lesions the correlations were not any more significant. Conclusions: We have observed that hemorrhagic punctate white matter lesions (SWI+ PWML) have risk factors, anatomical position and prognostic significance that differs with those of non-hemorrhagic ones, and that their presence is connected with lower gestational ages, as is known for other hemorrhagic lesions (GMH-IVH and CBH). It could be though useful to use this distinction in clinical practice. We have also observed that even low-grade lesions of all types have a negative influence on neurological outcome at 3 year of age, underlining the importance of precise diagnostics and elaboration of preventive strategies

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start

Brain volumes and developmental outcome in childhood following fetal growth restriction leading to very preterm birth

Background: Children born very preterm (PT) after fetal growth restriction (FGR) exhibit cognitive impairment at early school age. The relationship between neurodevelopmental impairment and attained regional brain volumes is unknown. Methods: We studied 23 preterm children with FGR (PT-FGR), 24 matched preterm children AGA (PT-AGA), and 27 matched term AGA children (T-AGA) by measuring brain volumes with magnetic resonance imaging at early school age. Cognitive and motor functions were assessed by the Wechsler Intelligence Scales for Children and the ABC-Movement score. Results: The mean (SD) full-scale IQ was 80 (17) in the PT-FGR group and 103 (12) in the PT-AGA group (p < 0.001). The PT-FGR group had lower mean total, gray matter, white matter, thalamic, cerebellar white matter, and hippocampal volumes as compared to the T-AGA group (p = 0.01, 0.04, 0.003, 0.002, 0.001, and 0.009, respectively). Brain volumes did not differ significantly between the PT groups. Reduction of hippocampal volume correlated with degree of growth restriction at birth (r = 0.46, p = 0.05). Neither the full-scale IQ nor the ABC movement score <5th percentile were related to brain volumes. Conclusion: Brain volumes as determined by MRI at early school age were primarily associated with degree of prematurity at birth and less with FGR. Regional brain volumes did not discriminate cognitive and motor function beyond that predicted by gestational age at birth

The effects of mild germinal matrix-intraventricular haemorrhage on the developmental white matter microstructure of preterm neonates: a DTI study

Objectives: To evaluate white matter (WM) microstructural changes in preterm neonates (PN) with mild germinal matrix-intraventricular haemorrhage (mGMH-IVH) (grades I and II) and no other associated MRI abnormalities, and correlate them with gestational age (GA) and neurodevelopmental outcome. Methods: Tract-based spatial-statistics (TBSS) was performed on DTI of 103 patients studied at term-equivalent age, to compare diffusional parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) between mGMH-IVH neonates (24/103) and controls matched by GA at birth and sex. The relationship between DTI abnormalities, GA and neurodevelopmental outcome assessed with Griffiths\u2019 Developmental Scale-Revised:0-2 was explored using TBSS and Spearman-correlation analysis (p &lt;.05). Results: Affected neonates had lower FA, higher RD and MD of the corpus callosum, limbic pathways and cerebellar tracts. Extremely preterm neonates (GA &lt; 29 weeks) presented more severe microstructural impairment (higher RD and MD) in periventricular regions. Neonates of GA 65 29 weeks had milder WM alterations (lower FA), also in subcortical WM. DTI abnormalities were associated with poorer locomotor, eye-hand coordination and performance outcomes at 24 months. Conclusions: WM microstructural changes occur in PN with mGMH-IVH with a GA-dependent selective vulnerability of WM regions, and correlate with adverse neurodevelopmental outcome at 24 months. Key Points: \u2022 DTI-TBSS analysis identifies WM microstructural changes in preterm neonates with mGMH-IVH. \u2022 Extremely preterm neonates with mGMH-IVH presented more severe impairment of WM microstructure. \u2022 Extremely preterm neonates with mGMH-IVH presented microstructural impairment of periventricular WM. \u2022 mGMH-IVH affects subcortical WM in preterm neonates with gestational age 65 29 weeks. \u2022 WM microstructural alterations are related to neurodevelopmental impairments at 24 months

Post-haemorrhagic hydrocephalus management: delayed neonatal transport negatively affects outcome

Post-haemorrhagic ventricular dilatation (PHVD) remains a major cause of brain injury in preterm infants. Cerebrospinal fluid drainage is often needed to decrease dilatation and prevent further damage. Like most European neonatal intensive care units (NICUs), we treat infants once the ventricular index (VI) has crossed the 97th percentile (p97) and 4mm line, as recently recommended

Nosological Differences in the Nature of Punctate White Matter Lesions in Preterm Infants

Background: The pathogenesis of punctuate white matter lesions (PWMLs), a mild form of white matter damage observed in preterm infants, is still a matter of debate. Susceptibility-weighted imaging (SWI) allows to differentiate PWMLs based on the presence (SWI+) or absence (SWI-) of hemosiderin, but little is known about the significance of this distinction. This retrospective study aimed to compare neuroradiological and clinical characteristics of SWI+ and SWI- PWMLs.Materials and Methods: MR images of all VLBW infants scanned consecutively at term-equivalent age between April 2012 and May 2018 were retrospectively reviewed, and infants with PWMLs defined as small areas of high T1 and/or low T2 signal in the periventricular white matter were selected and included in the study. Each lesion was analyzed separately and characterized by localization, organization pattern, and distance from the lateral ventricle. Clinical data were retrieved from the department database.Results: A total of 517 PWMLs were registered in 81 patients, with 93 lesions (18%) visible on SWI (SWI+), revealing the presence of hemosiderin deposits. On univariate analysis, compared to SWI- PWML, SWI+ lesions were closer to the ventricle wall, more frequently organized in linear pattern and associated with lower birth weight, lower gestational age, lower admission temperature, need for intubation, bronchopulmonary dysplasia, retinopathy of prematurity, and presence of GMH-IVH. On multivariate analysis, closer distance to the ventricle wall on axial scan and lower birth weight were associated with visibility of PMWLs on SWI (p = 0.003 and p = 0.0001, respectively).Conclusions: Our results suggest a nosological difference between SWI+ and SWI- PWMLs. Other prospective studies are warranted to corroborate these observations

Randomized Control Trial of Postnatal rhIGF-1/rhIGFBP-3 Replacement in Preterm Infants: Post-hoc Analysis of Its Effect on Brain Injury.

Background: Postnatal insulin-like growth factor-1 (IGF-1) replacement with recombinant human (rh)IGF-1 and IGF binding protein-3 (rhIGF-1/rhIGFBP-3) is being studied as a potential treatment to reduce comorbidities of prematurity. We have recently reported on a phase II, multicenter, randomized, controlled trial comparing postnatal rhIGF-1/rhIGFBP-3 replacement with standard of care (SOC) in extremely preterm infants (NCT01096784). Maximum severity of retinopathy of prematurity was the primary endpoint of the trial and presence of GMH-IVH/PHI one of the pre-specified secondary endpoints. Infants therefore received serial cranial ultrasound scans (CUS) between birth and term age. In this post-hoc analysis we present a detailed analysis of the CUS data of this trial and evaluate the effect of postnatal rhIGF-1/rhIGFBP-3 replacement on the incidence of different kinds of brain injury in extremely preterm infants. Methods: This report is an exploratory post-hoc analysis of a phase II trial in which infants <28 weeks gestational age were randomly allocated to rhIGF-1/rhIGFBP-3 or SOC. Serial cranial ultrasounds were performed between birth and term-equivalent age. Presence of germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH), periventricular hemorrhagic infarction (PHI), post-hemorrhagic ventricular dilatation, and white matter injury (WMI) were scored by two independent masked readers. Results: The analysis included 117 infants; 58 received rhIGF-1/rhIGFBP-3 and 59 received SOC. A trend toward less grade II-III GMH-IVH and PHI was observed in treated infants vs. SOC. A subanalysis of infants without evidence of GMH-IVH at study entry (n = 104) showed reduced progression to GMH-IVH in treated infants (25.0% [13/52] vs. 40.4% [21/52]; not significant). No effects of rhIGF-1/rhIGFBP-3 on WMI were observed. Conclusion: The potential protective effect of rhIGF-1/rhIGFBP-3 on the occurrence of GMH-IVH/PHI appeared most pronounced in infants with no evidence of GMH-IVH at treatment start

Neurodevelopmental consequences of preterm punctate white matter lesions: a systematic review

OBJECTIVES: To evaluate punctate white matter lesion (PWML) influence in preterm infants on the long-term neurodevelopmental outcome (NDO). METHODS: PubMed and EMBASE were searched from January 1, 2000, to May 31, 2021. Studies were included in which PWML in preterm infants on MRI around term-equivalent age (TEA) and NDO at ≥12 months were reported. Study and patient characteristics and NDO on motor, cognitive, and behavioral domains were extracted. The quality of studies was assessed using the Cochrane-approved Quality in Prognosis Studies tool. RESULTS: This analysis included nine studies with a total of 1655 patients. Mean incidence of isolated PWML was 22.1%. All studies showed a relationship between PWML and motor delay. Two studies found a significant correlation between cognitive and behavioral outcomes and PWML. Number and PWML location are related to severity and impairment types. LIMITATIONS: PWML were not always separately described from generalized WMI, only studies with imaging around TEA were included, and studies were heterogenic in design and quality. CONCLUSIONS: PWML is common in preterm infants and predictive of adverse NDO, in particular on motor outcomes and less on cognitive and behavioral outcomes. The type and severity of impairments are related to the number and location of PMWL. IMPACT: PWML is common in preterm infants and seems predictive of adverse NDO. DWI and SWI MRI sequences are informative because the different patterns suggest a difference in the underlying pathology. The type and severity of impairments are related to the number and location of PMWL. Our review can inform clinicians and parents about the NDO of preterm infants with a diagnosis of PWML. Prospective neuroimaging case-control cohort studies are recommended

Neurodevelopmental Outcome at 3 Years of Age in Very Low Birth Weight Infants According to Brain Development and Lesions

Background: During the last decades, severe brain lesions affecting very low birth weight (&lt;1500 gr, VLBW) infants were gradually substituted by milder lesions with debatable prognoses. Objective: The objective of this study is to define type, frequency and 3 years of neurodevelopmental outcome of prematurity-related brain lesions in a modern cohort of VLBW infants. Methods: VLBW infants admitted to our NICU in 5 years period with brain MRI at term-equivalent age were included. MRI scans were reviewed to identify and grade white matter lesions (WML), intraventricular hemorrhage (IVH), and cerebellar hemorrhage (CBH). Linear measurements of brain size, biparietal width (BPW) and trans-cerebellar diameter (TCD) were carried out. Total maturation score (TMS) was calculated. Developmental Coefficients (DQ) on Griffiths Scale at 3 years of age were compared between patients with different types and grades of lesions and patients without lesions; possible correlations between linear brain measurements, brain maturation and outcome were explored. Results: Study included 407 patients. Of them, 187 (46%) had at least one brain lesion on MRI, while 37 (9%) had severe lesions. The most frequent lesion was IVH (28%), followed by WML (21%) and CBH (17%). Mild and severe IVH, moderate and severe WML and all grades of CBH were related to worst outcome at 3 years. In patients without lesions, small BPW and small TCD were associated with worse outcomes. No correlations were observed between TMS and outcome. Conclusion: We have observed that even mild brain lesions have a negative influence on neurological outcome at 3 years of age