Melatonin vs. dexmedetomidine for sleep induction in children before electroencephalography.

Background and objectives: In children requiring electroencephalography (EEG), sleep recording can provide crucial information. As EEG recordings during spontaneous sleep are not always possible, pharmacological sleep-inducing agents are sometimes required. The aim of the study was to evaluate safety and efficacy of melatonin (Mel) and dexmedetomidine (Dex; intranasal and sublingual application) for sleep induction prior to EEG. Methods: In this prospective randomized study, 156 consecutive patients aged 1-19 years were enrolled and randomized by draw into melatonin group (Mel; n = 54; dose: 0.1 mg/kg), dexmedetomidine (Dex) sublingual group (DexL; n = 51; dose: 3 mcg/kg) or dexmedetomidine intranasal group (DexN; n = 51; dose: 3 mcg/kg). We compared the groups in several parameters regarding efficacy and safety and also carried out a separate analysis for a subgroup of patients with complex behavioral problems. Results: Sleep was achieved in 93.6% of participants after the first application of the drug and in 99.4% after the application of another if needed. Mel was effective as the first drug in 83.3% and Dex in 99.0% (p < 0.001); in the subgroup of patients with complex developmental problems Mel was effective in 73.4% and Dex in 100% (p < 0.001). The patients fell asleep faster after intranasal application of Dex than after sublingual application (p = 0.006). None of the patients had respiratory depression, bradycardia, desaturation, or hypotension. Conclusions: Mel and Dex are both safe for sleep induction prior to EEG recording in children. Dex is more effective compared to Mel in inducing sleep, also in the subgroup of children with complex behavioral problems. Clinical Trial Registration: Dexmedetomidine and Melatonin for Sleep Induction for EEG in Children, NCT04665453.

Multiple sclerosis in a 4-year-old boy: a case report and literature review.

Pediatric onset multiple sclerosis (POMS) in the very young is a very rare entity and presents a difficult diagnostic challenge due to overlapping signs and symptoms with other diseases. We present a 4-year-old boy who initially presented with right-sided hemiparesis and demyelinating lesions on MRI. Follow-up MRI examinations 3 and 6 months later revealed new demyelinating lesions. Ten months after initial presentation, he presented with right-sided hemiparesis, central facial nerve palsy on the right side and new demyelinating lesions on MRI. Two clinical events and new MRI lesions on follow-up MRIs confirmed the diagnosis of POMS. He was treated with rituximab and experienced no further relapses or radiological progression during the follow-up period.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Corrigendum: Prognostic value of various diagnostic methods for long-term outcome of newborns after hypoxic-ischemic encephalopathy treated with hypothermia.

[This corrects the article DOI: 10.3389/fped.2022.856615.].

Restraint stress during neonatal hypoxia-ischemia alters brain injury following normothermia and hypothermia.

Rodent models of neonatal hypoxic-ischemic (HI) injury require a subset of animals to be immobilized for continuous temperature monitoring during the insult and subsequent treatment. Restrained animals are discarded from the analysis due to the effect of restraint on the brain injury as first demonstrated by Thoresen et al 1996. However, the effects of restraint on responses to hypothermic (HT) post-insult therapy are not well described. We examine the effects of restraint associated with different probe placements on HI brain injury. We have conducted a meta-analysis of 23 experiments comparing probe rats (skin n = 42, rectal n = 35) and free-moving matched non-probe controls (n = 80) that underwent HI injury (left common carotid artery ligation and 90 min 8% O2 ) at postnatal day 7 (P7), followed by 5 h of NT (37°C) or HT (32°C). On P14, brain regions were analyzed for injury (by neuropathology and area loss), microglial reactivity and brain-derived neurotrophic factor (BDNF). HI injury was mitigated in NT skin and rectal probe rats, with greater neuroprotection among the rectal probe rats. Following HT, the skin probe rats maintained the restraint-associated neuroprotection, while brain injury was significantly exacerbated among the rectal probe rats. Microglial reactivity strongly correlated with the acquired injury, with no detectable difference between the groups. Likewise, we observed no differences in BDNF signal intensity. Our findings suggest a biphasic neuroprotection from restraint stress, which becomes detrimental in combination with HT and the presumed discomfort from the rectal probe. This finding is useful in highlighting unforeseen effects of common experimental designs or routine clinical management.

High incidence of multisystem inflammatory syndrome and other autoimmune diseases after SARS-CoV-2 infection compared to COVID-19 vaccination in children and adolescents in south central Europe.

OBJECTIVES: To estimate the incidence and describe the spectrum of inflammatory and autoimmune diseases linked to SARS-CoV-2 infection and COVID-19 vaccination in children from two neighbouring south central European countries. METHODS: We performed a multi-centre prospective cohort study of children under 18 years diagnosed with inflammatory/autoimmune diseases linked to SARS-CoV-2 infection or COVID-19 vaccination, who were admitted to the paediatric tertiary care hospitals in Slovenia and Friuli Venezia Giulia, Italy, from January 1, 2020, to December 31, 2021. Disease incidence was calculated based on laboratory-confirmed cases only. RESULTS: Inflammatory and autoimmune diseases linked to SARS-CoV-2 were diagnosed in 192 children (127 laboratory-confirmed), of whom 112 had multisystem inflammatory syndrome (MIS-C), followed by vasculitis, neurological and cardiac diseases. Calculated risk of MIS-C was 1 in 860 children after SARS-CoV-2 infection and cumulative incidence of MIS-C was 18.3/100,000 of all children. Fifteen children had severe COVID-19. Two patients with MIS-C and a patient with myositis presented after COVID-19 vaccination. All 3 had at presentation also a serologically proven recent SARS-CoV-2 infection. After MIS-C, nine patients were vaccinated against COVID-19 and 25 patients had a SARS-CoV-2 reinfection, without recurrence of MIS-C. CONCLUSIONS: Autoimmune diseases following SARS-CoV-2 infection in children were 8.5 times as common as severe COVID-19. MIS-C was the most common manifestation and its incidence in this predominantly white population was higher than previously reported. MIS-C does not seem to recur after SARS-CoV-2 reinfection or COVID-19 vaccination. Autoimmune diseases were much more common after SARS-CoV-2 infection than after COVID-19 vaccination.

Difficult to treat absence seizures in children: A single-center retrospective study.

Objectives: The aim of this study was to analyse the characteristics of typical absence seizures (AS), myoclonic AS and AS with eyelid myoclonia in children and to find associations between these characteristics and difficult to treat absence seizures (DTAS). Methods: This was a single-center retrospective study. Electronic health records of pediatric patients with a clinical diagnosis of AS treated at a single tertiary epilepsy center between January 2013 and June 2020 were reviewed. Clinical characteristics, seizure information, ASM, and therapeutic response of patients were recorded. All patients were followed up for at least 1 year. DTAS were defined as failure to achieve remission after treatment with at least 2 anti-seizure medications (ASM), regardless of whether remission was achieved eventually in the study period. Results: Data from 131 patients were available for analysis. Remission was achieved after the first ASM treatment in 81 (61.8%) patients, and eventually in 120 (91.6%) during the study period. Epilepsy was classified as DTAS in 18 (13.7%) patients. AS were more often difficult to treat in patients with myoclonic AS and AS with eyelid myoclonia (40.0%), compared with patients with typical AS (11.4%; p = 0.012, 95% CI 1.480-25.732). A positive family history of epilepsy (p = 0.046; 95% CI 1.021-8.572), a higher seizure frequency (p = 0.023, 95% CI 1.009-1.126) prior to ASM treatment, and longer time between seizure onset and treatment onset (p = 0.026; 95% CI 1.006-1.099) were also associated with DTAS. Significance: Our study suggests that several clinical characteristics of AS are associated with DTAS. One of these was the time between onset of AS and initiation of ASM treatment, which can be shortened with better care, suggesting that early diagnosis and treatment may improve prognosis in pediatric patients with AS. These findings remain to be confirmed in larger prospective studies.

Correlation between Phenotype and Genotype in CTNNB1 Syndrome: A Systematic Review of the Literature.

The CTNNB1 Syndrome is a rare neurodevelopmental disorder associated with developmental delay, intellectual disability, and delayed or absent speech. The aim of the present study is to systematically review the available data on the prevalence of clinical manifestations and to evaluate the correlation between phenotype and genotype in published cases of patients with CTNNB1 Syndrome. Studies were identified by systematic searches of four major databases. Information was collected on patients' genetic mutations, prenatal and neonatal problems, head circumference, muscle tone, EEG and MRI results, dysmorphic features, eye abnormalities, early development, language and comprehension, behavioral characteristics, and additional clinical problems. In addition, the mutations were classified into five groups according to the severity of symptoms. The study showed wide genotypic and phenotypic variability in patients with CTNNB1 Syndrome. The most common moderate-severe phenotype manifested in facial dysmorphisms, microcephaly, various motor disabilities, language and cognitive impairments, and behavioral abnormalities (e.g., autistic-like or aggressive behavior). Nonsense and missense mutations occurring in exons 14 and 15 were classified in the normal clinical outcome category/group because they had presented an otherwise normal phenotype, except for eye abnormalities. A milder phenotype was also observed with missense and nonsense mutations in exon 13. The autosomal dominant CTNNB1 Syndrome encompasses a wide spectrum of clinical features, ranging from normal to severe. While mutations cannot be more generally categorized by location, it is generally observed that the C-terminal protein region (exons 13, 14, 15) correlates with a milder phenotype.

Urine and Fecal 1H-NMR Metabolomes Differ Significantly between Pre-Term and Full-Term Born Physically Fit Healthy Adult Males.

Preterm birth (before 37 weeks gestation) accounts for ~10% of births worldwide and remains one of the leading causes of death in children under 5 years of age. Preterm born adults have been consistently shown to be at an increased risk for chronic disorders including cardiovascular, endocrine/metabolic, respiratory, renal, neurologic, and psychiatric disorders that result in increased death risk. Oxidative stress was shown to be an important risk factor for hypertension, metabolic syndrome and lung disease (reduced pulmonary function, long-term obstructive pulmonary disease, respiratory infections, and sleep disturbances). The aim of this study was to explore the differences between preterm and full-term male participants' levels of urine and fecal proton nuclear magnetic resonance (1H-NMR) metabolomes, during rest and exercise in normoxia and hypoxia and to assess general differences in human gut-microbiomes through metagenomics at the level of taxonomy, diversity, functional genes, enzymatic reactions, metabolic pathways and predicted gut metabolites. Significant differences existed between the two groups based on the analysis of 1H-NMR urine and fecal metabolomes and their respective metabolic pathways, enabling the elucidation of a complex set of microbiome related metabolic biomarkers, supporting the idea of distinct host-microbiome interactions between the two groups and enabling the efficient classification of samples; however, this could not be directed to specific taxonomic characteristics.

Prognostic Value of Various Diagnostic Methods for Long-Term Outcome of Newborns After Hypoxic-Ischemic Encephalopathy Treated With Hypothermia.

Introduction: Prediction of outcome in newborns with hypoxic-ischemic encephalopathy (HIE) has been modulated by hypothermia treatment (HT). We assessed the predictive value of diagnostic methods commonly used in neonates with HIE for short-term neurodevelopmental outcome and long-term neurological outcome. Materials and Methods: This longitudinal cohort study followed up 50 term newborns who underwent HT after HIE between July 2006 and August 2015, until preschool age. We estimated sensitivity and specificity for short-term neurodevelopmental outcome at 18 months and long-term neurological outcome at five years based on Amiel-Tison Neurological Assessment (ATNA), electroencephalography (EEG), and magnetic resonance imaging (MRI) performed in the neonatal period. Results: The accuracy of all neonatal methods tested was higher for long-term neurological outcome compared to the predictive accuracy for short-term neurodevelopmental outcome at 18-24 months. Sensitivity and specificity in predicting unfavorable long-term neurological outcome were: MRI (sensitivity 1.0 [95%CI 0.96-1.0]; specificity 0.91 [95%CI 0.86-1.0]), EEG (sensitivity 0.94 [95%CI 0.71-1.0]; specificity 1.0 [95% CI 0.89-1.0]), and ATNA (sensitivity 0.94 [95%CI 0.71-1.0]; specificity 0.91 [95%CI 0.76-0.98]). Conclusion: MRI is a powerful predictor of long-term neurological outcome when performed in the first week after HIE in HT treated infants, as are EEG and ATNA performed in the second or third week postnatally.

Dysmature patterns of newborn EEG recordings: Biological markers of transitory brain dysfunction or brain injury.

Perinatal hypoxic-ischemic brain injury is a major cause of non-progressive neurological deficits in children. Dysmature patterns can be seen in newborns' electroencephalograms (EEGs) and may have prognostic value for long-term outcomes. OBJECTIVE: To investigate the prognostic value of dysmature EEG patterns in term or near-term newborns. METHODS: Neonates with dysmature patterns in their first neonatal EEG, assessed during a 6-year period from January 2010 to December 2015, were included in the study. Their outcomes at their follow-ups in June 2019 (at the age of 3 years or more) were assessed, and the presence of neurological deficits and/or epilepsy was noted. RESULTS: We identified 347 neonates with video-EEG recordings during the observed period, in which 10 neonates had dysmature patterns in their first EEG. Eight were born at term and two were born late preterms, born at the 35 and 36-week gestational age. The reasons for admission were HIE grade I in 2 patients, grade II in 6 neonates, and heart problems in 2 patients. The second EEG was recorded at different time intervals, in 7 infants between 1 and 6 weeks; three infants had second EEG much later and were excluded from the study. Six of seven infants showed normal background activity (BA), and five had sharp waves over different regions, all six had normal developmental outcomes. One child with dysrhythmic pattern in the second EEG was diagnosed with genetic encephalopathy, developed spastic cerebral palsy and died due to severe pneumonia at the age of 6 years. CONCLUSION: Dysmature patterns may reflect transitory brain dysfunctions. Neonatal EEG tests remain reliable and important diagnostic tool in the very first weeks of life, particularly due to the availability of sequential EEG recordings and interpretations.

Children with Arteriovenous Malformations of the Central Nervous System: A Retrospective Study of 12 Pediatric Cases from a Single Tertiary Center in Slovenia.

BACKGROUND Arteriovenous malformation (AVM) of the central nervous system (CNS) is a developmental condition that consists of a focal mass of interconnected veins and arteries. This retrospective study was conducted at the only tertiary center in Slovenia and included 12 pediatric cases of AVM of the CNS, diagnosed between 2000 and 2020. MATERIAL AND METHODS The patients were collected based on the ICD coding system. All available medical documentation was reviewed. RESULTS Our cohort included 6 boys and 6 girls. The mean age of patients was 9.1 years, range 1 month to 16.3 years. The estimated incidence of pediatric AVM of the CNS in Slovenia is 0.22/100 000 children per year. Ten patients had brain AVM and 2 patients had spinal AVM. At first presentation, 7 patients presented with intracerebral hemorrhage, 2 with focal neurological deficits, 1 with epilepsy, 1 with chronic headache, and 1 patient was asymptomatic. Two patients had their first hemorrhage after an already-established diagnosis of AVM. Endovascular embolization was performed in 50%, surgical resection in 33%, and conservative treatment in 17% of patients. Five patients had no residual neurological sequelae, 6 had some neurological deficits, and 1 patient died. Complete obliteration of AVM was achieved in 3 patients treated with surgery. They all had a favorable outcome, with no or mild deficit. CONCLUSIONS The study findings support that early diagnosis and management are required to prevent neurological deterioration and vessel rupture from AVM. Endovascular embolization was the most commonly used procedure. Complete obliteration was associated with good neurological outcome.

Effects of Pre-Term Birth on the Cardio-Respiratory Responses to Hypoxic Exercise in Children.

Pre-term birth is associated with numerous cardio-respiratory sequelae in children. Whether these impairments impact the responses to exercise in normoxia or hypoxia remains to be established. Fourteen prematurely-born (PREM) (Mean ± SD; gestational age 29 ± 2 weeks; age 9.5 ± 0.3 years), and 15 full-term children (CONT) (gestational age 39 ± 1 weeks; age 9.7 ± 0.9 years), underwent incremental exercise tests to exhaustion in normoxia (FiO2 = 20.9%) and normobaric hypoxia (FiO2 = 13.2%) on a cycle ergometer. Cardio-respiratory variables were measured throughout. Peak power output was higher in normoxia than hypoxia (103 ± 17 vs. 77 ± 18 W; p < 0.001), with no difference between CONT and PREM (94 ± 23 vs. 86 ± 19 W; p = 0.154). VO2peak was higher in normoxia than hypoxia in CONT (50.8 ± 7.2 vs. 43.8 ± 9.9 mL·kg-1·min-1; p < 0.001) but not in PREM (48.1 ± 7.5 vs. 45.0 ± 6.8 mL·kg-1·min-1; p = 0.137; interaction p = 0.044). Higher peak heart rate (187 ± 11 vs. 180 ± 10 bpm; p = 0.005) and lower stroke volume (72 ± 13 vs. 77 ± 14 mL; p = 0.004) were observed in normoxia versus hypoxia in CONT, with no such differences in PREM (p = 0.218 and >0.999, respectively). In conclusion, premature birth does not appear to exacerbate the negative effect of hypoxia on exercise capacity in children. Further research is warranted to identify whether prematurity elicits a protective effect, and to clarify the potential underlying mechanisms.

The impact of birthweight on the development of cerebral palsy: A population-based matched case-control study.

BACKGROUND: Cerebral palsy (CP) is a common cause of physical impairment in children, especially in newborns who are small for gestational age (SGA). AIMS: The aim of our study was to investigate the association between birth weight and the risk of developing CP, controlling for gestational age and plurality. STUDY DESIGN: This retrospective, observational, case-control study was based on Slovenian Registry of Cerebral Palsy (SRCP) and Slovenian National Perinatal Information System (NPIS) data for the period 2002 to 2010. SUBJECTS: For each pregnancy that resulted in the birth of the newborn(s) who later developed CP (n = 254), three pregnancies with newborns who did not develop CP (n = 762) were selected and matched for gestational age and plurality. OUTCOME MEASURES: Diagnosis of CP was made at age 5 years or older by a developmental pediatrician trained in child neurology or a child neurologist using standard measures. RESULTS: Risk of CP increased progressively as birth weight percentiles fell below the 50th centile, with children in the lowest percentiles at greatest risk. Birth weight percentiles traditionally classified as SGA were an independent risk factor for developing CP, with an odds ratio of 2.43 (95% confidence interval 1.57, 3.73). CONCLUSIONS: The results of this study suggest that the risk for developing CP is inversely related to birth weight, even at birth weights that do not meet the standard definitions of SGA. SYNOPSIS - STUDY QUESTION: Does birth weight represent a potential risk factor for the development of cerebral palsy (CP) when controlling for gestational age and plurality? WHAT'S ALREADY KNOWN: Newborns who are small for gestational age (SGA) are at higher risk of developing CP according to published studies. However, different definitions of SGA (birth weight below the 10th, 5th, or 3rd percentile for gestational age) have been used by researchers and clinicians, making it difficult to compare studies. WHAT THIS STUDY ADDS: This study suggests that the risk of developing CP is inversely related to birth weight, even at birth weights that do not meet standard definitions of SGA.

Post-exercise accumulation of interstitial lung water is greater in hypobaric than normobaric hypoxia in adults born prematurely.

We aimed to gauge the interstitial lung water accumulation following moderate-intensity exercise under normobaric and hypobaric hypoxic conditions in a group of preterm born but otherwise healthy young adults. Sixteen pre-term-born individuals (age = 21±2yrs.; gestational age = 29±3wk.; birth weight = 1160±273 g) underwent two 8 -h hypoxic/altitude exposures in a cross-over manner: 1) Normobaric hypoxic exposure (NH; FIO2 = 0.142±0.001; PIO2 = 90.6±0.9 mmHg) 2) Hypobaric hypoxic exposure (HH; terrestrial high-altitude 3840 m; PIO2 = 90.2±0.5 mmHg). Interstitial lung water was assessed via quantification of B-Lines (using lung ultrasound) before (normoxia) and after 4-h and 8-h of respective exposures. At each time point, B-Lines were quantified before (Pre) and immediately after (Post) a 6-min moderate-intensity exercise. The baseline B-lines count were comparable between both conditions (P = 0.191). A higher B-lines count was noted at Pre-H4 in HH versus NH (P = 0.0420). At Post-H8 B-lines score was significantly higher in HH (4.6 ± 1.6) than in NH (3.1 ± 1.4; P = 0.0073). Furthermore, at this time point, a significantly higher number of individuals with B-line scores ≥5 was observed in HH (n = 7) than in NH (n = 3; P = 0.0420). These findings suggest that short moderate-intensity exercise provokes a significant increase in the interstitial lung water accumulation after 8 h of exposure to terrestrial but not simulated altitude (≈3840 m) in prematurely born adults. Further work is needed to elucidate the exact mechanisms of (moderate-intensity) exercise-induced interstitial lung water accumulation in this population and directly compare the obtained data to full-term born adults.

Long-Term Effects of Prematurity on Resting Ventilatory Response to Hypercapnia.

Manferdelli, Giorgio, Benjamin J. Narang, Mathias Poussel, Damjan Osredkar, Grégoire P. Millet, and Tadej Debevec. Long-term effects of prematurity on resting ventilatory response to hypercapnia. High Alt Med Biol. 22:420-425, 2021. Background: This study investigated the resting ventilatory response to hypercapnia in prematurely born adults. Materials and Methods: Seventeen preterm and fourteen full-term adults were exposed to normoxic hypercapnia (two 5-minute periods at 3% and 6% carbon dioxide [CO2] interspersed by 5-minute in normoxia). Pulmonary ventilation ([Formula: see text]) and end-tidal partial pressure of CO2 (Petco2) were measured continuously. Results: No difference in lung function was observed between preterm and full-term adults. Petco2 was lower in preterm than in full-term adults (p < 0.05) during normoxia. During exposure to 3% CO2, both [Formula: see text] and Petco2 increased in a similar way in preterm and full-term adults. However, at the end of the 6% CO2 period, there was a significantly higher [Formula: see text] in preterm compared with full-term adults (30.2 ± 7.5 vs. 23.7 ± 4.5 L/min, p < 0.0001), whereas no difference was observed for Petco2 (46.9 ± 2.1 vs. 50.6 ± 2.1 L/min, p = 0.99). Breath frequency was higher in preterm than in full-term adults (17.9 ± 4.0 vs. 12.8 ± 3.5 b/min, p < 0.01) during 6% CO2 exposure. Conclusions: Although data suggest that prematurity results in resting hypocapnia, the exact underlying mechanisms remain to be elucidated. Moreover, preterm adults seem to have increased chemosensitivity to hypercapnia.

Mind the Gap: Acetazolamide Prolonged Periods without Paralysis in a Girl with Andersen-Tawil Syndrome.

We present a case report of a 13-year-old girl with Andersen-Tawil Syndrome (ATS), a rare genetic disorder which is characterized by dysmorphic features, ventricular arrhythmias, and frequent episodes of muscle paralysis that interfere with daily activities and social engagement. After the introduction of off-label treatment with acetazolamide periods without paralysis lengthened, our patient became more independent of the help of her parents and required a wheelchair less frequently, thus improving her social life. Based on our experience, we recommend a trial of acetazolamide in patients with ATS.

Reye Syndrome with Severe Hyperammonemia and a Good Neurological Outcome.

BACKGROUND Reye syndrome (RS) is a rare life-threatening condition combining acute noninflammatory encephalopathy and acute liver failure with an absence of defined etiology. We present a case of fulminant RS that had a good neurological outcome. CASE REPORT A 4-year-old previously healthy boy had no history of acetylsalicylic acid (ASA) use, nor had he been diagnosed with any inborn errors of metabolism. RS was preceded by a mild viral infection, possibly caused by human bocavirus, which has not been previously implicated in RS. He presented with a combination of a very high concentration of ammonia but only mildly elevated aminotransferases and mild hypoglycemia. Computed tomography (CT) of the head additionally showed diffuse cerebral edema with tentorial herniation. The extensive metabolic evaluation did not confirm any inborn errors of metabolism to explain the etiology. We provided optimal treatment of severe hyperammonemia (>500 µmol/L) and cerebral edema, including high doses of arginine chloride, sodium benzoate, hemodialysis, mild hypothermia, and supportive care. He has been followed up for over 4 years. The patient recovered completely, with no long-term psycho-cognitive or neurological sequelae. CONCLUSIONS Although extremely rare, hyperammonemia and RS should be considered in cases of an acute encephalopathy to be treated as soon and as decisively as possible to enable a good outcome.

Children with cavernous malformations of the central nervous system.

BACKGROUND: Cavernous malformations (CM) of the central nervous system (CNS) are a rare pathology in the pediatric population that may present with an acute onset of severe neurological symptoms. OBJECTIVE: The aim of our study was to evaluate the clinical presentation, family history, genetic background, radiological features, treatment and outcome of children with CM. METHODS: This observational cohort study included all children with CM of the CNS diagnosed in the period 2000-2020 at University Children's Hospital in Ljubljana, Slovenia. Whole exome sequencing was utilized. RESULTS: We identified a cohort of 20 children with CM (mean age 9.3 years, range: 10 days-18.4 years). In our cohort, 16 patients were symptomatic and 4 were asymptomatic; 7 patients had a solitary lesion, and 13 had multiple lesions. Children with multiple lesions become symptomatic at an earlier age compared with children with solitary lesions. We identified five families with familiar cavernous malformation (FCM) syndrome affecting two or more generations; FCM represented 65% of all pediatric cases identified in our study. We confirmed a mutation in FCM associated genes in all but one patient with multiple lesions, with the KRIT1 mutation being the most common. CONCLUSION: Multiple CM lesions and symptomatic brainstem lesions are associated with worse neurological deficits in pediatric patients. Not all cases of multiple lesions can be linked to mutations in KRIT1, CCM2, or PDCD10, which may indicate that there are other as yet unidentified genes associated with FCM.

Clinical and Radiological Characteristics of Non-Benign Pineal Cyst Lesions in Children.

Background: With the increasing availability and advances in brain imaging, pineal cyst lesions (PCL) are becoming a common finding in the pediatric population. In the absence of evidence-based guidelines, optimal diagnostic and therapeutic approaches have not been established, and there is a risk of under- or overtreatment of these patients. Objectives: The aim of our study was to evaluate the clinical presentation and radiological features of PCL in a cohort of pediatric patients and to identify clinical parameters more commonly associated with neoplasms in the pineal region. In addition, the prevalence of PCL in the pediatric population of Slovenia was estimated. Methods: In this observational, cohort study, children treated at University Children's Hospital, Ljubljana, Slovenia in the period 1997-2016 were included if PCL was found on brain imaging. We analyzed indications for referral to a neurologist, clinical signs and symptoms, radiological features, treatment and outcome. Results: The cohort consisted of 143 children with PCL. Pineocytoma was suspected in 31 children (21.7%). Six children underwent surgery - pineocytoma was confirmed in two cases and germinoma in one (2/3 of these children had signs of increased intracranial pressure (ICP), while PCL was benign in the remaining 4 cases. Only 2 PCL enlarged during the study period, both <2mm, none of these children developed neoplasm. Two children had PCL >20mm in diameter; both showed signs of increased ICP, one patient was found to have a germinoma of the pineal region, while the other had no neoplasm. Conclusions: Most PCL do not change their features during radiological follow-up and even atypical PCL are very rarely associated with a malignant neoplasm of the pineal region. A PCL larger than 20 mm and signs of increased ICP were identified as potential markers for selecting patients at risk.