Alessandro Parodi

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients

OBJECTIVEnTo describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).nnnMETHODSnCases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.nnnRESULTSnThe study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.nnnCONCLUSIONnOur findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

Different gestational ages and changing vulnerability of the premature brain

Abstract In recent decades, there has been a general increase in survival rates of preterm and low birth weight infants, but this overall decrease in perinatal mortality has not been accompanied by a decrease in long-term physical and mental disability. In order to reduce the long-term sequelae of prematurity and to establish preventive measures, it is important to identify risk factors since the main determinant of specific vulnerability to different types of lesions is gestational age. The regional tissue vulnerability at a given gestational age is probably determined by the local metabolic requirements together with specific cell characteristics and their level of maturation. In this article, we discuss the most common neonatal cerebral lesions (cerebellar haemorrhage, germinal matrix intraventricular haemorrhage, periventricular leukomalacia, arterial ischaemic stroke, cerebral vein sinus thrombosis and hypoxic-ischaemic encephalopathy) related to the gestational age-dependent vulnerability of the premature brain.

Low-grade intraventricular hemorrhage: is ultrasound good enough?

Abstract Objective: To assess diagnostic accuracy of cranial ultrasonography (CUS) in detecting low-grade (i.e. grade I and grade II) germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) in very low birth weight (VLBW) infants. Methods: Among VLBW infants who were admitted to Gaslini Children’s Hospital neonatal intensive care unit between January and November 2012, patients who underwent both serial CUS since birth and magnetic resonance susceptibility-weighted imaging (SWI) at term-equivalent age were included in this retrospective study. Diagnostic accuracy of CUS in detecting low-grade GMH-IVH was assessed in terms of sensitivity and specificity by comparing it to SWI, which was used as the gold-standard technique. Results: Sixty VLBW infants were included in the study. Sensitivity of CUS in detecting low-grade GMH-IVH was low (60%), whilst specificity was 100%. Conclusions: In the present study, CUS sensitivity in detecting grade I–II GMH-IVH proved to be surprisingly low, in contrast with specificity. In other words, we suggest that low-grade GMH-IVH may be underdiagnosed in VLBW infants when assessed exclusively with CUS.

Differences in subependymal vein anatomy may predispose preterm infants to GMH–IVH

Background and purpose The anatomy of the deep venous system plays an important role in the pathogenesis of brain lesions in the preterm brain as shown by different histological studies. The aims of this study were to compare the subependymal vein anatomy of preterm neonates with germinal matrix haemorrhage–intraventricular haemorrhage (GMH–IVH), as evaluated by susceptibility-weighted imaging (SWI) venography, with a group of age-matched controls with normal brain MRI, and to explore the relationship between the anatomical features of subependymal veins and clinical risk factors for GMH–IVH. Methods SWI venographies of 48 neonates with GMH–IVH and 130 neonates with normal brain MRI were retrospectively evaluated. Subependymal vein anatomy was classified into six different patterns: type 1 represented the classic pattern and types 2–6 were considered anatomic variants. A quantitative analysis of the venous curvature index was performed. Variables were analysed by using Mann-Whitney U and χ2 tests, and a multiple logistic regression analysis was performed to evaluate the association between anatomical features, clinical factors and GMH–IVH. Results A significant difference was noticed among the six anatomical patterns according to the presence of GMH–IVH (χ2=14.242, p=0.014). Anatomic variants were observed with higher frequency in neonates with GMH–IVH than in controls (62.2% and 49.6%, respectively). Neonates with GMH–IVH presented a narrower curvature of the terminal portion of subependymal veins (p<0.05). These anatomical features were significantly associated with GMH–IVH (p<0.05). Conclusion Preterm neonates with GMH–IVH show higher variability of subependymal veins anatomy confirming a potential role as predisposing factor for GMH–IVH.

Accuracy of ultrasound in assessing cerebellar haemorrhages in very low birthweight babies

Objective To assess diagnostic accuracy of cranial ultrasound (CUS) performed through the anterior fontanelle (AF) and mastoid fontanelle (MF) in detecting cerebellar haemorrhages (CBH) in very low birthweight (VLBW) infants. Setting Third-level neonatal intensive care unit (NICU). Design VLBW infants consecutively admitted at Gaslini Children’s Hospital between February 2012 and September 2013 underwent both CUS and MR susceptibility-weighted imaging (SWI). CUS was performed at days 1, 2, 3 and 7 after birth, then weekly until term-equivalent age. All CUS examinations were performed through AF and MF using an 8u2005Mhz convex probe. Depending on the size, CBHs were classified as massive, limited or microhaemorrhages. Diagnostic accuracy of CUS through AF and MF in detecting all types of CBHs was assessed by comparing it with SWI, used as the gold-standard technique. Results 140 VLBW infants were included. CUS sensitivity in detecting massive CBH through both AF and MF was excellent (100%). However, CUS sensitivity through AF dropped down to 16.7% (95% CI 1% to 46%) in cases of limited CBH, with sensitivity through MF remaining good (83.3%; 95% CI 53% to 100%). None of the microhaemorrhages diagnosed by SWI was identified by CUS, despite the use of MF. Specificity of CUS in detecting all degrees of CBH through both AF and MF was excellent (100%). Conclusions Routine use of MF allows a better detection of limited CBH when compared with AF. Overall sensitivity of CUS in detecting CBH is low when microhaemorrhages are included. In other words, microhaemorrhages proved to be undetectable by CUS.

Variability of Cerebral Deep Venous System in Preterm and Term Neonates Evaluated on MR SWI Venography

BACKGROUND AND PURPOSE: The anatomy of the deep venous system is characterized by a great variability that might play an important role in the pathogenesis of brain lesions in the preterm brain. The aim of this study was to compare the anatomy of cerebral subependymal veins evaluated on SWI venography in 3 groups of neonates with normal brain MR imaging (very preterm [gestational age <32 weeks], moderate-to-late preterm [gestational age ≥32 to ≤37 weeks], and term neonates [gestational age >37 weeks]) and to evaluate the influence of preterm birth on development of subependymal veins. MATERIALS AND METHODS: SWI venographies of 84 very preterm, 31 moderate-to-late preterm, and 50 term neonates were retrospectively evaluated. Subependymal vein anatomy was classified into 6 different patterns: type 1 represented the classic pattern and types 2–6 were considered anatomic variants. A χ2 test was used to evaluate differences between the distributions of subependymal vein patterns. RESULTS: A significant difference (P = .011) was noticed between the 6 patterns based on gestational age. Type 1 was more frequent in term neonates (68%) than in both very preterm (41.7%) and moderate-to-late preterm neonates (56.5%). Anatomic variants were more common in very preterm neonates (66%) than in both moderate-to-late preterm (41%) and term neonates (36%). Interhemispheric asymmetry was more frequent in very preterm (59.5%) and moderate-to-late preterm neonates (51.6%) than in term neonates (34%; P = .017). Sex and monozygotic twin birth did not significantly affect the frequency of subependymal vein patterns (P = .0962). CONCLUSIONS: The deep venous system of the neonatal brain shows a large spectrum of anatomic variants with higher variability of subependymal vein anatomy in preterm than term neonates, likely related to the influence of the preterm birth and epigenetic factors on subependymal vein development.

Incidental findings on routine brain MRI scans in preterm infants

Objective Many neonatal intensive care units (NICUs) have adopted the practice of performing routine brain MRI in very low birth weight (VLBW) infants at term-equivalent age in order to better evaluate prematurity-related acquired lesions. A number of unexpected brain abnormalities of potential clinical significance can be visualised on routine scans as well. The aim of our study was to describe these incidental findings (IFs) in a VLBW population and to assess their clinical significance. Study design We retrospectively reviewed a series of brain MRI scans performed in VLBW infants consecutively admitted to our NICU between November 2011 and November 2014. IFs on brain MRI, which were not detected by cranial ultrasound nor suspected clinically, were registered. Clinical significance of IF was assessed in terms of need of further diagnostic or therapeutic interventions. Results IFs were detected in 28 out of 276 VLBW infants (10.1%). In total, 21 cases (7.6%) required an intervention, which was only diagnostic in 16 cases, and both diagnostic and therapeutic in 5 cases. In the remaining seven cases (2.5%), no further action was considered necessary. Conclusions This study suggests that IFs on brain MRI of VLBW infants are not rare. In our population, most of them required a diagnostic or therapeutic intervention. The need and appropriateness of routine MRI scanning in VLBW at term-equivalent age are still subject of debate, and we believe our data can contribute meaningfully to this discussion.

Macrophage activation syndrome in juvenile systemic lupus erythematosus

OBJECTIVEnTo describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).nnnMETHODSnCases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.nnnRESULTSnThe study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.nnnCONCLUSIONnOur findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

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

AbstractObjectivesTo 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.MethodsTract-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’ Developmental Scale-Revised:0-2 was explored using TBSS and Spearman-correlation analysis (p < .05).ResultsAffected neonates had lower FA, higher RD and MD of the corpus callosum, limbic pathways and cerebellar tracts. Extremely preterm neonates (GA < 29 weeks) presented more severe microstructural impairment (higher RD and MD) in periventricular regions. Neonates of GA ≥ 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.ConclusionsWM 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• DTI-TBSS analysis identifies WM microstructural changes in preterm neonates with mGMH-IVH.n • Extremely preterm neonates with mGMH-IVH presented more severe impairment of WM microstructure.n • Extremely preterm neonates with mGMH-IVH presented microstructural impairment of periventricular WM.n • mGMH-IVH affects subcortical WM in preterm neonates with gestational age ≥ 29 weeks.n • WM microstructural alterations are related to neurodevelopmental impairments at 24 months.

Quantitative susceptibility map analysis in preterm neonates with germinal matrix-intraventricular hemorrhage: QSM Analysis in Neonates With Germinal Matrix Hemorrhage

Germinal matrix‐intraventricular hemorrhage (GMH‐IVH) is a common form of intracranial hemorrhage occurring in preterm neonates that may affect normal brain development. Although the primary lesion is easily identified on MRI by the presence of blood products, its exact extent may not be recognizable with conventional sequences. Quantitative susceptibility mapping (QSM) quantify the spatial distribution of magnetic susceptibility within biological tissues, including blood degradation products.