Background and Objectives:Disease-causing variants in the syntaxin-binding protein 1 (STXBP1) gene are among the most common genetic causes of developmental and epileptic encephalopathies and are associated with a wide phenotypic spectrum. Qualitative neuroimaging studies are usually unrevealing or uncover variable MRI findings, including cortical atrophy, thin/dysmorphic corpus callosum (CC), hypo/delayed myelination, and focal cortical dysplasia (FCD). Methods:We used quantitative MRI methods to estimate abnormal brain properties of the cortical mantle and volume of subcortical structures in patients with STXBP1 encephalopathy and age- and sex-matched controls.We performed a region-of-interest group statistical analysis between patients with STXBP1 encephalopathy and controls by multivariable linear regression models to identify morphometric patterns and to evaluate the effect of the group (patients/controls) on morphometric features. We conducted a longitudinal analysis to estimate the volumetric changes in 4 patients with serial MRI scans at different ages. We calculated the association between the structural alterations and the known STXBP1 expression levels and explored associations between morphometric and volumetric features and clinical findings (age at seizure onset, intellectual disability [ID]) and genetic variants. Results:Our analysis included 24 patients and 48 controls and revealed widespread cortical thickening, reduced frontal and occipital surface area, and reduced white matter (left/right hemisphere p value = 0.005/0.022) and CC (p value < 0.050) volumes. The longitudinal analysis highlighted that brain growth trends were lower than the average trend in the control cohort. In patients with more severe ID, we observed a significantly increased volume of the lateral ventricles (left/right p value = 0.049/0.030) and CSF (p value = 0.019). Patients with missense variants exhibited more altered morphometric values and more severe reductions of white-matter volumes, possibly because of a dominant negative effect of variants. Two patients were operated for intractable focal seizures, and the histopathologic substrate was FCD-I. Discussion:The altered cortical patterns and WM reductions we observed in STXBP1 encephalopathy might be the structural counterpart of the widespread impaired neurotransmitter release caused by a dysfunctional syntaxin-binding protein. The 2 histopathologic observations we describe, bring to 4 the number of reported patients with STXBP1 encephalopathy and FCD-I, suggesting cortical dyslamination as the architectural substrate for the abnormal morphometric parameters and reduced surface areas.

Background/Objectives: Neonates with hypoxic–ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) frequently develop coagulation abnormalities and bleeding complications, yet data on transfusion burden and its clinical correlates in this population remain limited. Materials and Methods: We performed a secondary analysis of a retrospective single-center cohort of neonates with HIE treated with TH between 2014 and 2022. Transfusion burden was defined as receipt of at least one blood component and coagulation/plasma products during hospitalization and the total number of transfusion episodes. Demographic, perinatal, biochemical, and clinical severity variables were collected. Univariable and multivariable logistic regression analyses were used to identify factors independently associated with transfusion exposure. Brain magnetic resonance imaging (MRI) findings were compared between transfused and non-transfused infants. Results: Among 142 included neonates, 74 (52.1%) received at least one blood product. The median number of transfusion episodes among transfused infants was 2 (IQR 1–3). Fresh frozen plasma and prothrombin complex concentrate were the most frequently administered products. Transfused infants showed higher markers of illness severity. In multivariable analysis, clinically visible bleeding (adjusted odds ratio [aOR] 12.95, 95% CI 1.34–124.97) and need for respiratory support (aOR 2.98, 95% CI 1.19–7.45) remained independently associated with transfusion exposure. Pathological brain MRI findings, including intracranial bleeding and hypoxic–ischemic injury, were more frequent among transfused infants. Conclusions: blood components and coagulation/plasma-derived products transfusions are common in neonates with HIE undergoing TH and appear to primarily reflect underlying disease severity. These findings highlight the need for optimized, evidence-based transfusion strategies in this vulnerable population.

Background/Objectives: Edwardsiella tarda is a rare Gram-negative pathogen that uncommonly infects humans. Neonatal infections are extremely rare but often severe, with a high incidence of central nervous system (CNS) complications. Case presentation: We report a term neonate born via spontaneous vaginal delivery who developed systemic signs of infection within 18 h of life. Blood and cerebrospinal fluid (CSF) cultures grew Edwardsiella tarda. CSF analysis revealed severe meningoencephalitis. Maternal stool culture was also positive for E. tarda, suggesting vertical transmission. Despite initial systemic antibiotic therapy with ampicillin, gentamicin, and ceftriaxone, neuroimaging revealed progressive multifocal brain abscesses. The infant underwent a series of neurosurgical procedures, including bilateral drainage of abscesses, Rickham reservoir placement and ventriculoperitoneal shunting. A revised antibiotic regimen, including systemic meropenem and trimethoprim-sulfamethoxazole plus intrathecal gentamicin, was administered. At six months, the infant showed mild motor delay with lower limb hypertonia and was under close neurosurgical and developmental follow-up. Methods: We conducted a literature review of 12 published neonatal E. tarda infections, including our case. Results: Most infected infants presented within 72 h of life and exhibited CNS involvement. Mortality was 25%, and 44% of survivors experienced long-term neurologic sequelae. Conclusions: Edwardsiella tarda infection in neonates is rare but potentially devastating. Early suspicion, culture confirmation, aggressive antibiotic therapy, and multidisciplinary care, including neurosurgical management, are essential for improving outcomes.

Background: Listeria monocytogenes infection during pregnancy remains an underrecognized cause of severe neonatal disease, frequently leading to central nervous system (CNS) involvement with high mortality and long-term neurological sequelae. Case presentation: We report a case series of four neonates with confirmed neonatal listeriosis and neurological complications, managed in a tertiary neonatal intensive care unit (NICU). Clinical features, microbiological findings, neuroimaging, treatments, and outcomes were analyzed. Our cases presented with early-onset disease and severe clinical courses, including sepsis, meningitis, ventriculitis, hydrocephalus, and seizures. Neuroimaging revealed extensive CNS injury, ranging from intraventricular hemorrhage to multiloculated hydrocephalus. Outcomes varied from near-normal neurodevelopment to profound neurological impairment, despite appropriate antimicrobial therapy. A narrative review of previous cases of neonatal listeriosis was also performed to contextualize our findings. Conclusions: Neonatal listeriosis remains associated with severe neurological morbidity. Early recognition, advanced neuroimaging, multidisciplinary management, and preventive maternal strategies are essential to improve outcomes.

Aicardi-Goutières syndrome (AGS) and genes-related interferonopathies are a group of multisystem disorders involving the central nervous system, caused by pathogenic variants in genes regulating nucleic acid metabolism and type I interferon signaling, leading to chronic interferon overproduction.This retrospective multicenter study analyzed the efficacy and safety of Janus kinase 1/2 (JAK1/2) inhibitors in 12 patients treated with Baricitinib or Ruxolitinib, compared with 20 untreated patients.Treatment showed improvement in immunological and dermatological symptoms, while the impact on neurological manifestations was limited and heterogeneous, with greater benefits in patients with mild or intermediate phenotypes and earlier treatment initiation. Neuroroimaging analyses in untreated patients showed radiological improvements equal to or greater than those treated, raising doubts about the true impact of JAK 1/2 inhibitors on the neuroradiological course. Adverse events were rare and mild, confirming the favorable safety profile of this treatment. The results suggest that the pathogenetic complexity of AGS goes beyond the JAK-STAT pathway, highlighting the need for larger prospective studies to identify subgroups most likely to benefit from this therapeutic approach and to refine treatment strategies.

Tubulinopathies constitute a growing and heterogeneous class of disorders caused by pathogenic variants in genes encoding for tubulins, the structural components of microtubules. These conditions encompass a broad spectrum of neurological manifestations, most commonly including structural brain malformations and, less frequently, neurodegenerative disorders. In addition to brain diseases, tubulinopathies also include non-neurological conditions, such as female meiotic infertility and bleeding disorders. Among tubulin genes, TUBB, encoding the class I β-tubulin, has been associated with a wide range of clinical conditions, primarily including neurodevelopmental delay, structural brain abnormalities, and skin creases. More recently, TUBB has also been linked to inherited macrothrombocytopaenia, suggesting a broader, yet still incompletely defined, role of this β-tubulin in haematopoiesis and platelet biogenesis. In this study, we aim to investigate pathogenic mechanisms of a novel frameshift variant in TUBB (c.628dup; p.Ile210AsnfsTer40), identified in a subject affected by thrombocytopaenia and neurological involvement. Functional analyses demonstrated that the p.Ile210AsnfsTer40 TUBB mutation leads to the production of a truncated β-tubulin with reduced protein stability and aberrant subcellular localization. The mutant protein showed impaired interaction with α-tubulin and kinesin family member 1 A (KIF1A), suggesting defective microtubule assembly and microtubule-mediated intracellular transport. Furthermore, the inhibition of the proteasome degradative pathway resulted in a marked increase of the mutant TUBB, indicating altered proteostasis and enhanced degradation of the truncated tubulin. Finally, we showed that the p.Asp249Val substitution in TUBB, previously associated with macrothrombocytopaenia, similarly reduces protein stability, weakens interaction with α-tubulin, and impairs TUBB incorporation into microtubules. This study associates the novel heterozygous truncating p.Ile210AsnfsTer40 variant in TUBB with a multisystem disorder characterized by haematological and neurological manifestations, expanding the phenotypic spectrum of TUBB-related diseases. Our findings indicate that reduced protein stability and functional impairment of β-tubulin represent key pathogenic mechanisms underlying this condition. Lastly, our experimental evidence further supports the implication of TUBB dysfunctions in haematological abnormalities, offering additional insight into the molecular basis and clinical variability of tubulin-related disorders.

Background Migraine accounts for most primary headaches in children and adolescents and is related to cortical and connectivity changes. However, the underlying mechanisms remain unclear. Morphometric similarity mapping has not yet been applied to children and adolescents with migraine.Methods Eighty-three patients (6-17 years) with migraine without aura and 81 age- and sex-matched controls were retrospectively included. High-resolution 3D T1-weighted and diffusion-weighted magnetic resonance imaging scans were processed to extract cortical morphometric parameters and compute morphometric similarity networks (MSN). Global and regional MSN differences were assessed between patients and controls, and across subgroups defined by sex, attack frequency and migraine-associated symptoms.Results Patients showed significant MSN alterations, particularly in temporal and cingulate regions. Sex emerged as the strongest factor influencing MSN architecture, with additional modulations linked to attack frequency and clinical symptoms. Affected pathways encompassed the executive control, nociceptive and default mode networks.Conclusions Migraine in children and adolescents is associated with widespread MSN abnormalities, likely reflecting cortical reorganization mechanisms. Male and female patients appear to engage distinct neural "orchestras", each emphasizing different network sections (sensory-affective in males and cognitive-attentive in females) to produce a shared clinical experience. These findings highlight sex as a key determinant of migraine neurobiology in developmental age.

Diaphragmatic paralysis (DP) in neonates is a rare yet potentially life-threatening cause of respiratory distress, often resulting from obstetric trauma or cardiac surgery. This report presents two distinct cases of bilateral DP: one following a dystocic delivery with associated brachial plexus involvement, and the other linked to a genetic mutation (SYNGAP1) in a neonate with no birth trauma. Diagnosis was established through imaging, fluoroscopy, electromyography, and genetic testing. In both cases, conservative management was initially pursued; however, due to persistent respiratory failure, invasive interventions were required. The first patient underwent bilateral diaphragmatic plication with favorable outcomes, while the second required tracheostomy due to poor response to non-invasive ventilation with good outcome. These cases highlight the diagnostic and therapeutic challenges of neonatal DP, emphasizing the need for individualized treatment strategies in the absence of standardized guidelines. Early diagnosis and a multidisciplinary approach are crucial to optimize respiratory outcomes and reduce complications from prolonged mechanical ventilation.

BackgroundCongenital syphilis (CS) remains a global public health concern, with rising incidence even in high-income countries. In Italy, a higher risk has been reported among primigravidae and younger mothers with late or missed prenatal screening. While neurological involvement in CS is well known, it is rarely reported in preterm infants, where it may be severe and atypical.Case presentationA male preterm infant, delivered at 32 weeks via emergency cesarean due to abnormal fetal monitoring and breech position, was admitted to our NICU with intraventricular hemorrhage, midline shift, and hydrocephalus, requiring neurosurgery. He later developed a metaphyseal bone lesion; Staphylococcus aureus was found in blood cultures. Despite antibiotics, persistent thrombocytopenia and infectious symptoms led to further testing, revealing congenital syphilis with neurological involvement and osteomyelitis and osteochondritis of the distal ulna and radio from an undetected maternal treponemal infection during pregnancy. Penicillin therapy produced slow recovery, but the newborn developed epilepsy and spastic tetraplegia by 24 months. Genetic and metabolic tests were negative. Literature review rarely shows similar CS cases, especially in preterm infants.ConclusionThis case highlights the relevance of universal maternal syphilis screening and early neonatal evaluation. Maternal Treponema pallidum infection during pregnancy can result in preterm birth and may be associated with neurological complications, such as hemorrhages, seizures, and motor impairment, which can require multidisciplinary management and long-term follow-up.

BACKGROUND AND PURPOSE:Single large-scale mitochondrial deletion syndrome (SLSMD) comprises devastating mitochondrial diseases often classified into 3 major clinical syndromes: Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), and Pearson syndrome (PS). Nevertheless, there remains large clinical variability and overlap among these SLSMD groups. Therefore, further stratification is required for more precise prognostication and clinical management. Through detailed description and analysis of longitudinal neuroimaging changes, we sought to determine the neuroradiologic hallmarks of SLSMDs and define their expected imaging progression to further delineate their natural history. MATERIALS AND METHODS:A retrospective, longitudinal study of 40 children with SLSMDs at 3 mitochondrial disease centers was performed. MRI review assessed the prevalence and progression of brain lesions in different regions with statistical significance testing and Kaplan-Meier analysis. Hierarchical cluster analysis was performed for involved brain regions to stratify findings into imaging phenotype groups. RESULTS:Among 40 patients with SLSMD (median age 9.26 years; interquartile range: 5.16-13.1), 67.5% had KSS, 15% had KSS with a prior history of PS (PS→KSS), and 10% had PS only. A well-delineated phenotype could not be specified for 1 (2.5%) and 2 (5%) individuals who had CPEO-plus (CPEO + extraocular symptoms). Regardless of presentation, initial MRI of patients with KSS revealed lesions within selective areas of the upper brainstem tegmentum. Follow-up MRIs in 26 patients showed well-defined progression along other select brainstem and white matter regions. Log-rank tests demonstrated varying onset times by lesion type. Cluster analysis revealed 2 distinct neuroimaging groups: 1) KSS, CPEO-plus, and PS→KSS versus 2) PS and not otherwise specified individuals. KSS, CPEO-plus, and PS→KSS showed indistinguishable neuroimaging features regardless of the initial clinical presentation. CONCLUSIONS:We describe the first comprehensive longitudinal neuroimaging pattern analysis in a multicenter, international SLSMDs disease pediatric cohort, delineating a predictable progression of brain lesions, regardless of clinical phenotype.

Artificial intelligence (AI) is revolutionarily shaping the entire landscape of medicine and particularly the privileged field of radiology, since it produces a significant amount of data, namely, images. Currently, AI implementation in radiology is continuously increasing, from automating image analysis to enhancing workflow management, and specifically, pediatric neuroradiology is emerging as an expanding frontier. Pediatric neuroradiology presents unique opportunities and challenges since neonates’ and small children’s brains are continuously developing, with age-specific changes in terms of anatomy, physiology, and disease presentation. By enhancing diagnostic accuracy, reducing reporting times, and enabling earlier intervention, AI has the potential to significantly impact clinical practice and patients’ quality of life and outcomes. For instance, AI reduces MRI and CT scanner time by employing advanced deep learning (DL) algorithms to accelerate image acquisition through compressed sensing and undersampling, and to enhance image reconstruction by denoising and super-resolving low-quality datasets, thereby producing diagnostic-quality images with significantly fewer data points and in a shorter timeframe. Furthermore, as healthcare systems become increasingly burdened by rising demands and limited radiology workforce capacity, AI offers a practical solution to support clinical decision-making, particularly in institutions where pediatric neuroradiology is limited. For example, the MELD (Multicenter Epilepsy Lesion Detection) algorithm is specifically designed to help radiologists find focal cortical dysplasias (FCDs), which are a common cause of drug-resistant epilepsy. It works by analyzing a patient’s MRI scan and comparing a wide range of features—such as cortical thickness and folding patterns—to a large database of scans from both healthy individuals and epilepsy patients. By identifying subtle deviations from normal brain anatomy, the MELD graph algorithm can highlight potential lesions that are often missed by the human eye, which is a critical step in identifying patients who could benefit from life-changing epilepsy surgery. On the other hand, the integration of AI into pediatric neuroradiology faces technical and ethical challenges, such as data scarcity and ethical and legal restrictions on pediatric data sharing, that complicate the development of robust and generalizable AI models. Moreover, many radiologists remain sceptical of AI’s interpretability and reliability, and there are also important medico-legal questions around responsibility and liability when AI systems are involved in clinical decision-making. Future promising perspectives to overcome these concerns are represented by federated learning and collaborative research and AI development, which require technological innovation and multidisciplinary collaboration between neuroradiologists, data scientists, ethicists, and pediatricians. The paper aims to address: (1) current applications of AI in pediatric neuroradiology; (2) current challenges and ethical considerations related to AI implementation in pediatric neuroradiology; and (3) future opportunities in the clinical and educational pediatric neuroradiology field. AI in pediatric neuroradiology is not meant to replace neuroradiologists, but to amplify human intellect and extend our capacity to diagnose, prognosticate, and treat with unprecedented precision and speed.

Exclusive breastfeeding (eBF) in infancy appears to offer a developmental advantage for children's brains compared to formula-fed counterparts. Existing research has predominantly focused on global brain measures (i.e., total white/grey matter volumes) or on limited sets of specific brain regions, in selected age groups, leaving uncertainties about the impact of eBF on the overall structural connectomes. In this cross-sectional study encompassing participants from childhood to adulthood, partial least squares correlations (PLSC) were employed to assess white and grey matter volumes. Furthermore, a network analytic approach was used to estimate the structural connectome based on cortical thickness data. The results revealed that eBF duration correlated with increased white matter volumes in children and with the volume of the medial orbital gyrus in adults. Structural connectome analyses demonstrated heightened anatomical connectivity in eBF children, evidenced by enhanced network density and local/global efficiency, along with increased node degree and local efficiency in frontal and temporal lobes. Similarly, eBF in adults was associated to an improved node connectivity in the frontal lobe. These findings imply a lasting impact of eBF on brain morphometry and structural connectivity. Childhood benefits include heightened white matter development, while in adulthood, eBF may contribute to reduced neural loss associated with aging and enhanced connectivity, particularly in frontal regions.

This study focuses on the proteomic analysis of cerebrospinal fluid (CSF) in a patient with stage III retinoblastoma (RB) with the aim to identify molecular changes associated with central nervous system (CNS) relapse. The child received systemic chemotherapy and intrathecal topotecan as CNS prophylaxis, along with enucleation of the left eye. After two chemotherapy cycles, CNS relapse occurred, evidenced by positive CSF findings and magnetic resonance imaging (MRI) showing leptomeningeal involvement at the anterior skull base. The child’s condition deteriorated, and two months later, he died due to progressive CNS disease. The aim of the study was to analyze serial CSF samples collected at different stages of treatment, as well as a control sample, to identify differences in CSF protein expression profiles during CNS RB relapse. Using mass spectrometry, a total of 1,029 proteins were identified across all CSF samples, samples were analyzed in duplicate ensuring technical replication. An unsupervised heatmap revealed 46 differentially expressed proteins. Over-regulated proteins in CSF-RB samples were primarily involved in inflammation, extracellular matrix remodeling, epithelial mesenchymal transition initiation, migration, invasion, and cellular metabolism (PON1, RNPEP, MCAM, NEGR1, NID1, SERPINA1, FAT2, RELN, NEGR1, and SEZ6). These processes are key drivers of cancer progression and metastasis. Proteomic analysis could be valuable in identifying proteins modulated in CSF during disease progression in RB patients, offering potential for new prognostic biomarkers.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social interaction, communication, and repetitive behaviors. Neuroimaging studies have revealed structural and functional neural changes in individuals with ASD compared to healthy subjects. Objectives: This study aimed to investigate brain network structural connectivity in ASD using Morphometric Similarity Network (MSN) analysis. Methods: Data from the Autism Brain Imaging Data Exchange (ABIDE) were analyzed, comprising 597 individuals with ASD and 644 healthy controls. Structural connectivity was assessed using cortical morphometric features. Global and regional network indices, including the density index, node degree, node strength, and clustering coefficients, were evaluated. Results: Among the global network indices, when using a threshold value of 0.4, ASD patients compared to HCs showed a lower density (p = 0.041) and higher negative clustering (p = 0.0051) coefficients. For regional network indices, ASD patients showed a lower bilateral superior frontal cortices degree (left hemisphere: p = 0.014; right hemisphere: p = 0.0038) and strength (left: p = 0.017; right: p = 0.018). Additionally, they showed higher negative clustering coefficients in the bilateral superior frontal cortices (left, p = 0.0088; right, p = 0.0056) and bilateral pars orbitalis (left, p = 0.016; right, p = 0.0006), as well as lower positive clustering in the bilateral frontal pole (left, p = 0.03; right, p = 0.044). Conclusions: These findings highlight significant alterations in both global and regional brain network organization in ASD, which may contribute to the disorder’s cognitive and behavioral manifestations. Future studies are needed to investigate the pathophysiological mechanisms underlying these structural connectivity changes, to inform the development of more targeted and individualized therapeutic interventions for individuals with ASD.

TRRAP encodes a multidomain pseudokinase involved in histone acetyltransferase complexes. TRRAP pathogenic variants were linked to neurodevelopmental disorders, intellectual disability, congenital anomalies, and hearing loss. We report on three unrelated patients with TRRAP missense variants. Patient #1, a girl with severe intellectual disability, autism features, and preaxial polydactyly, displays the c.5575C>T, p.(Arg1859Cys) variant. Patient #2, a boy with developmental delay and facial anomalies, harbors the c.5647G>A, p.(Gly1883Arg) variant. Patient #3, a girl with developmental delay, epilepsy, and renal artery stenosis, carries the c.8572C>T, p.(Arg2858Trp) variant. These new cases broaden the TRRAP phenotypic spectrum, updating genotype-phenotype correlations. Osteoclast differentiation in Patient #1 and TRRAP expression in osteoclasts and osteoblasts were analyzed, leading to the assumption of a role of TRRAP in bone remodeling and in the observed skeletal anomalies.

Liver transplantation (LTx) is increasingly used in Urea Cycle Defects (UCDs) to prevent recurrent hyperammonemia and related neurological irreversible injury. Among UCDs, argininosuccinate lyase deficiency (ASLD) has a more complex phenotype than other UCDs, with long-term neurocognitive deficits. Therefore, the role of LTx in ASLD is still debated. The impact of LTx on nine patients with early-onset ASLD was assessed through pre- and post-LTx clinical, neuropsychological, MRI and biochemical evaluations. After LTx, no episodes of metabolic decompensations were reported. Neuropsychological evaluations documented significant improvement in cognitive/developmental functioning especially in patients transplanted in early childhood. Improvements were also highlighted in daily living skills and emotional-behavioral problems, with a reduction in attention disturbances and somatic complaints. Movement disorders resolved after LTx in patient transplanted in early childhood. Any patients developed epilepsy with stability of EEG alterations after LTx. A positive effect of LTx on other disease-related outcomes such as growth, diet, medications, hospitalizations, and long-term ASLD-related complications was highlighted. The primary biomarker argininosuccinic acid dramatically reduced in plasma after transplantation with a decreasing trend in CSF at long-term follow-up. Moreover, health-related quality of life improved after LTx, especially when assessed through MetabQoL, a tool designed for intoxication diseases such as ASLD. In conclusion, our study showed a global beneficial impact of LTx in early-onset ASLD patients to avoid episodes of hyperammonemia, and improve neurocognitive outcome, adaptive and behavioral deficits when performed in early childhood with a dramatic benefit in terms of quality of life.

Congenital malformations of the eye represent a wide and heterogeneous spectrum of abnormalities that may be part of a complex syndrome or be isolated. Ocular malformation severity depends on the timing of the causative event during eye formation, ranging from the complete absence of the eye if injury occurs during the first weeks of gestation, to subtle abnormalities if the cause occurs later on. Knowledge of ocular malformations is crucial to performing a tailored imaging protocol and correctly reporting imaging findings. Together with the ophthalmologic evaluation, imaging may help frame ocular malformations and identify underlying genetic conditions. The purpose of this pictorial review is to describe the imaging features of the main ocular malformations and the related ophthalmologic findings in order to provide a clinico-radiological overview of these abnormalities to the clinical radiologist. Sight is a crucial sense for children to explore the world and relate with their parents from birth. Vision impairment or even blindness secondary to ocular malformations deeply affects children’s growth and quality of life.

Biallelic variants in the 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene have been described in 2020 as able to cause a progressive disorder with variable clinical presentation, ranging from severe neonatal-onset encephalopathy or infantile-onset neurodegeneration with progressive spasticity and brain white matter abnormalities (NEDSWMA), to milder manifestation of adolescent-onset pure hereditary spastic paraplegia (HSP) classified as SPG83.1 We report the case of a 16.5-year-old girl, who firstly came at our attention at 6 months of age for mild lower limb hypertonia and poor social interaction. During the first 3 years of age, she manifested normal motor development with language delay. At around 4 years of age, she developed an ataxic-spastic syndrome with regression of developmental milestones up to loss of autonomous ambulation at age 5.5 years. Initial brain MRI was unrevealing but progressive cerebro-cerebellar atrophy appeared and mild bilateral posterior white matter hyperintensity persisted (Fig. 1A–I). Genetic testing performed over years (eg, karyotype analysis, targeted NGS panel for Hereditary Spastic Paraparesis and Spastic Ataxias) was unremarkable. At 14.5 years, she presented acute onset of ptosis, bilateral divergent strabismus and diplopia. Neither infections nor stressful events were reported in the preceding period. During this episode, a further brain MRI showed a Wernicke-like pattern with bilateral and symmetric FLAIR hyperintensity and T1 hypointensity, without DWI-ADC restriction and contrast enhancement, of superior colliculi, mesial longitudinal fasciculi, periaqueductal region, interthalamic adhesion and thalamic mesial profile (Fig. 1L–P). Lumbar puncture excluded inflammatory and infectious causes. Multimodal (ie, visual, brainstem auditory and motor) evoked potential revealed an altered conduction of retrochiasmatic optic pathway, upper pons abnormalities and increased central conduction time of pyramidal tracts connected with lower limbs. Metabolic (blood lactate, acylcarnitine, aminoacids, sphingolipids, urinary organic acids, cerebrospinal fluid lactate, aminoacids and organic acids) and vitamin (serum A, B1, B2, B6, B12) screening were all unrevealing. Ex-adiuvantibus treatment with oral steroids (ie, prednisone 1.3 mg/kg/die, successively tapered in 2 weeks) and antioxidant vitamins (ie, CoQ10, B1, B2 and biotin) was delivered. Resolution of ptosis and diplopia was apparent within 1 week and complete ocular symptoms remission was observed at subsequent visits after 4 months. Brain MRI follow-up showed improvement of the Wernicke-like pattern after 2 and 12 months (not shown) and its resolution after 2 years (Fig. 1Q–U). Genetic testing with trio-whole exome sequencing revealed the homozygous c.365delG (p.Ser122fsTer8) variant in HPDL gene (NM_032756.2) inherited from her healthy heterozygous father, classified as likely pathogenetic (class IV) according to ACMG criteria, and not present in current literature nor in variant databases. Successively, SNP array disclosed a long contiguous stretch of homozygosity involving the entire chromosome 1 that was confirmed to have paternal origin indicating paternal isodisomy. HPDL-related disease has been currently described in 71 subjects from 50 families.1-8 Here we have reported a further case with an intermediate form2 characterized by early-onset progressive ataxic-spastic tetraparesis with neuroimaging feature of progressive brain atrophy with cerebellar predominance, who experienced a sudden episode of ophthalmoplegia with Wernicke-like pattern during acute phase. Clinical (ie, ophthalmoplegia and ptosis) and neuroimaging (ie, Wernicke-like pattern) findings resolved over time after steroidal and antioxidant therapy. It is difficult to determine any possible causal link between either of the two treatments and clinical-radiological improvement, also considering that reversible neuroimaging findings have already been described in HPDL patients. In particular, original description suggested three possible MRI patterns1: type I with striatal (ie, Leigh-like) reversible changes with possible lactate peak, and persistent white matter anomalies; type II with predominant relapsing cortical, brain stem, thalamic or inferior colliculi anomalies (similar to the case presented in our study); type III with spinal cord involvement. Pure HSP cases may have normal brain MRI.2 Unexplained acute episodes of encephalopathy have also been reported in HPDL-related disorder,2 mostly in the severe phenotype, and misdiagnosed with autoimmune disease such as acute disseminated encephalomyelitis.2, 9 However, clinical features and association with neuroimaging anomalies have not been accurately described yet. Abnormalities in conjugated eye movements have already been reported,4, 10 but to our knowledge, association between acute ophthalmoplegia and Wernicke-like neuroimaging pattern is a novel finding. HPDL is an intronless single-exon gene that encodes the 4-hydroxyphenylpyruvate dioxygenase-like protein, which is expressed in mitochondria, and it has been described to play a role in complex II activity and CoQ10 byosynthesis.10 Implication of HPDL protein in mitochondrial function and thiamine role in Krebs cycle,11 together with similar neuroimaging findings during acute decompensation in both HPDL-related disorder and Wernicke encephalopathy, suggest a possible shared mechanism of energetic dysfunction that still needs to be assessed with novel basic research studies that could clarify HPDL-related disorders pathophysiology. Finally, broad genetic testing such as exome sequencing is becoming increasingly important in most (neuro-)genetic disorders including HSPs, due to continuous recognition of novel disease-causing genes, which may not be detected by non-updated targeted sequencing. HPDL is one of these and it should be considered in both pure and complex forms, where pyramidal signs can be accompanied by ataxia and other transient focal signs up to acute-onset encephalopathy, and by neuroimaging features of brain atrophy, with hyperintense and possible reversible anomalies of white and deep gray matter, brainstem and spinal cord. (1) Research project: A. Conception. B. Data Collection; (2) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. J.S.: 2A. D.L.: 1A, 2B. L.T.: 1B, 2B. V.O.: 1B, 2B. A.D.: 2B. E.B.: 2B. F.N.: 1A, 2A. FN and EB are members of the European Reference Network for Rare Neurological Diseases-Project ID No 739510. Ethical Compliance Statement: Submission of the manuscript has been approved by our Institution (approval number RAP-2023-0003). Patient's parents have signed the written informed consent for genetic analyses and for participation in study research. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict Of Interest: This work was supported by the Italian Ministry of Health with "Current Research funds". The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. The data that supports the findings of this study are included in this article.

BACKGROUND: Encephalopathy of different etiologies in infants is often the reason for central respiratory insufficiency which eventually leads patients to the Pediatric Intensive Care Unit. Magnetic resonance imaging (MRI) and brainstem auditory evoked potentials (BAEPs) may be useful to identify brainstem alterations among patients with respiratory insufficiency of central origin. MRI is a compulsory technique to identify brain abnormalities, but may fail to detect brainstem lesions of small dimensions. BAEPs play a highly sensitive role on brainstem dysfunction identification because of the generators of different peaks which are related to specific brainstem structures.METHODS: The study included ten infants affected by encephalopathy of different etiologies and early neurological respiratory failure. To evaluate BAEPs, the surface electrodes were placed at the vertex (Cz) and on each mastoid side.RESULTS: All subjects presented alteration of BAEPs. The brain MRI revealed selective injury of the brainstem in four patients and supratentorial alterations in six patients.CONCLUSIONS: The early identification of brainstem lesions in mechanically ventilated infants with encephalopathy may reduce the weaning off mechanical ventilation's attempt numbers and provide early informative discussions with families and clinical caregivers about treatment options, such as tracheostomy, long term ventilation and the reduction of their length of PICU stay. Furthermore, this would support the evaluation process concerning the affected children, their families and the needs of other social groups, including health systems.