Background: Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%. Methods: We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG. Results: All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065). Conclusions: Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.

Recent evidence has shown that patterns of cortico-cortical functional synchronization are consistently traceable by the end of the third trimester of pregnancy. The involvement of subcortical structures in early functional and cognitive development has never been explicitly investigated, notwithstanding their pivotal role in different cognitive processes. We address this issue by exploring subcortico-cortical functional connectivity at rest in a group of normally developing fetuses between the 25th and 32nd weeks of gestation. Results show significant functional coupling between subcortical nuclei and cortical networks related to: (i) sensorimotor processing, (ii) decision making, and (iii) learning capabilities. This functional maturation framework unearths a Cognitive Development Blueprint, according to which grounding cognitive skills are planned to develop with higher ontogenetic priority. Specifically, our evidence suggests that a newborn already possesses the ability to: (i) perceive the world and interact with it, (ii) create salient representations for the selection of adaptive behaviors, and (iii) store, retrieve, and evaluate the outcomes of interactions, in order to gradually improve adaptation to the extrauterine environment.

Human cytomegalovirus (HCMV) is the leading infectious agent causing congenital disabilities. The risk of HCMV transmission to the fetus in pregnant women receiving immunosuppressive agents is unknown. We describe two cases of pregnant women with evidence of pre-conception HCMV protective immunity receiving azathioprine for ulcerative colitis or systemic lupus erythematosus. Both women reactivated the HCMV and transmitted the infection to the fetuses. One newborn showed unilateral hearing deficits and brain abnormalities while the other was asymptomatic. The mother of the symptomatic newborn had low levels of total and HCMV-specific blood CD4⁺ T cells. Women receiving immunosuppressive agents deserve information about the risk of HCMV congenital infection and should be monitored for HCMV infection during pregnancy. Their newborns should be screened for HCMV congenital infection.

Altered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero. To study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI). Prospective single-centre cohort study. A sample of 31 singleton pregnancies at 28–34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient. Fetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. First, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. Fetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially “connecting” different PTB phenotypes.