Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study.

BACKGROUND: Gadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients. OBJECTIVE: This subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years). MATERIALS AND METHODS: The GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration. RESULTS: The GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04-0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population. CONCLUSION: Gadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults.

Opsoclonus-myoclonus syndrome after adenovirus infection.

Autoimmune and paraneoplastic movement disorders are rare in childhood. Diagnosis often relies on clinical manifestations and clinicians' recognition. A 22-month-old girl at onset of opsoclonus-myoclonus syndrome (OMS) was followed for 8 years. Adenovirus (type C subtype 3) infection coincided with manifestation. Data on treatment, imaging and follow-up are provided. In the spinal fluid, elevated anti-rubella antibodies and oligoclonal bands were detected. An autoimmune process affecting mainly cerebellar neurons was revealed immunohistochemically. Moderately intense long-term immunosuppressive therapy resulted in a favorable clinical outcome. A video demonstrated severe OMS manifestations at onset, followed by nearly complete recovery after treatment. We describe the association of a parainfectious OMS and adenovirus infection; laboratory results indicate a non-specific humoral process affecting mainly cerebellar neurons. Our video documentation will aid to recognize this rare movement disorder and to initiate early treatment.

The Gini coefficient: a methodological pilot study to assess fetal brain development employing postmortem diffusion MRI.

BACKGROUND: Diffusion-weighted imaging (DWI) is important in the assessment of fetal brain development. However, it is clinically challenging and time-consuming to prepare neuromorphological examinations to assess real brain age and to detect abnormalities. OBJECTIVE: To demonstrate that the Gini coefficient can be a simple, intuitive parameter for modelling fetal brain development. MATERIALS AND METHODS: Postmortem fetal specimens(n = 28) were evaluated by diffusion-weighted imaging (DWI) on a 3-T MRI scanner using 60 directions, 0.7-mm isotropic voxels and b-values of 0, 150, 1,600 s/mm(2). Constrained spherical deconvolution (CSD) was used as the local diffusion model. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) and complexity (CX) maps were generated. CX was defined as a novel diffusion metric. On the basis of those three parameters, the Gini coefficient was calculated. RESULTS: Study of fetal brain development in postmortem specimens was feasible using DWI. The Gini coefficient could be calculated for the combination of the three diffusion parameters. This multidimensional Gini coefficient correlated well with age (Adjusted R(2) = 0.59) between the ages of 17 and 26 gestational weeks. CONCLUSIONS: We propose a new method that uses an economics concept, the Gini coefficient, to describe the whole brain with one simple and intuitive measure, which can be used to assess the brain's developmental state.

Invasive pneumococcal diseases in children and adolescents--a single centre experience.

BACKGROUND: S. pneumoniae is a major cause of meningitis, pneumonia and sepsis in children. In 2006 universal pneumococcal vaccination was recommended in Germany for all children up to their second birthday. We have compared the prevalence and outcome of IPD at a single hospital before and after the introduction of vaccination. FINDINGS: 55 cases of IPD were identified over an 11 year period. Almost half of the patients were younger than 2 years of age. Most of the children were affected by pneumonia. The second highest incidence seen was for meningitis and sepsis. 17 patients exhibited additional complications. Significant pre-existing and predisposing disorders, such as IRAK 4 defect, ALPS or SLE were identified in 4 patients. Complete recovery was seen in 78% of affected children; 11% had a fatal outcome and 11% suffered from long term complications. Only 31% overall had been vaccinated. The most common serotype was 14. Serotypes not covered by any of the current vaccines were also found. Antibiotic treatment commenced with cephalosporins in over 90%. CONCLUSION: Frequency of IPD in our hospital did not decrease after initiation of the pneumococcal vaccination. This might be due to vaccinations not being administered satisfactorily as well as to poor education about the need of the vaccination. Pre-existing diseases must be monitored and treated accordingly and rare deficiencies taken into account when IPD takes a foudroyant course. In addition, antibiotic stewardship has been initiated at this hospital centre as a consequence of the high cephalosporin use detected in this study.

Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies.

BACKGROUND: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is caused by germ line mutations in the PTEN gene. Symptoms include cancer predisposition, immune deviations, and lipomas/lipomatosis. No causal standard therapy is available. We describe a therapeutic attempt with the mammalian target of rapamycin (mTOR) inhibitor sirolimus for a PHTS patient suffering from thymus hyperplasia and lipomatosis. We furthermore assessed the in vitro effects of sirolimus and other inhibitors on lipoma cells of the patient. METHODS: The patient underwent clinical and blood examinations and whole-body magnetic resonance imaging to assess tumor sizes. Lipoma cells of the patient were incubated with inhibitors of the phosphoinositide-3-kinase (PI3K)/AKT/mTOR signaling pathway to analyze the effects on proliferation, adipocyte differentiation, and survival in vitro. RESULTS: Sirolimus treatment improved somatic growth and reduced thymus volume. These effects diminished over the treatment period of 19 mo. Sirolimus decreased lipoma cell proliferation and adipocyte differentiation in vitro but did not cause apoptosis. PI3K and AKT inhibitors induced apoptosis significantly. CONCLUSION: Sirolimus treatment led to an improvement of the patient's clinical status and a transient reduction of the thymus. Our in vitro findings point to PI3K and AKT inhibitors as potential treatment options for patients with severe forms of PHTS.

Wide spectrum of clinical manifestations in children with tuberous sclerosis complex--follow-up of 20 children.

UNLABELLED: TSC is a multisystem genetic disorder predisposing to multiple organ manifestations and developmental problems. Clinical follow-up of patients remains a challenge for the caring paediatrician. METHODS: We performed a retrospective analysis of clinical manifestations, diagnostic and therapeutic data in 20 children with the diagnosis of tuberous sclerosis complex (TSC) to answer the following questions: are the clinical guidelines and imaging strategies appropriate to discover complications, are there significant early predictors of long-term prognosis, what is the age range for signs and symptoms to occur. RESULTS: Cardiac rhabdomyoma were present in 18 children and occurred as earliest manifestation. 8 of these exhibited associated arrhythmia or congenital cardiac anomalies. Seizures combined with cortical tubers and subependymal nodules occurred in 18 patients and were most likely to start in infancy, which was associated with later cognitive impairment. Cutaneous manifestations (15 children) occurred in late childhood and school age, whilst renal angiomyolipomas (11) developed in puberty. DISCUSSION: The clinical course and imaging strategies are compared with data from previous studies. A review of TSC in regard to the multiple manifestations is provided.

Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C.

The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died at the age of 11 months. A homozygousLMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing. Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.

Contrast-enhanced magnetic resonance imaging in pediatric patients: review and recommendations for current practice.

Magnetic resonance imaging (MRI), frequently with contrast enhancement, is the preferred imaging modality for many indications in children. Practice varies widely between centers, reflecting the rapid pace of change and the need for further research. Guide-line changes, for example on contrast-medium choice, require continued practice reappraisal. This article reviews recent developments in pediatric contrast-enhanced MRI and offers recommendations on current best practice. Nine leading pediatric radiologists from internationally recognized radiology centers convened at a consensus meeting in Bordeaux, France, to discuss applications of contrast-enhanced MRI across a range of indications in children. Review of the literature indicated that few published data provide guidance on best practice in pediatric MRI. Discussion among the experts concluded that MRI is preferred over ionizing-radiation modalities for many indications, with advantages in safety and efficacy. Awareness of age-specific adaptations in MRI technique can optimize image quality. Gadolinium-based contrast media are recommended for enhancing imaging quality. The choice of most appropriate contrast medium should be based on criteria of safety, tolerability, and efficacy, characterized in age-specific clinical trials and personal experience.

A case report and review of the literature of laparoscopic sleeve gastrectomy in morbidly obese adolescents: beyond metabolic surgery and visceral fat reduction.

OBJECTIVE: Data on safety, effectiveness and amelioration of metabolic comorbidities are scarce for adolescents undergoing laparoscopic sleeve gastrectomy (LSG). METHODS: Data on a 17 year-old female who underwent LSG due to morbid obesity and quantification of visceral adipose tissue (VAT)/hepatic fat (HF) by MRI scan are presented. In addition, a review of the literature related to LSG in adolescent obesity is provided [search terms: laparoscopic sleeve gastrectomy, adolescence, obesity]. RESULTS: Pre-existing comorbidities in our patient included insulin resistance, NASH (HF: 28%) and hyperuricemia. BMI dropped from 52.9 kg/m(2) to 40.4 and 35.0 kg/m(2) after 6 and 24 months, respectively, following LSG. VAT dropped by 49.2% and by 71.5% within 6 and 24 months, accompanied by a decrease of HF to 1.53% and to 0.85%, respectively. Improvements of metabolic parameters towards normal range, which were reached within 6 months following LSG, could be maintained for 2 years. The review of the literature revealed that 9 original papers on LSG in adolescent obesity are available to date, ranging from single case presentations to case series of 108 patients and including children and adolescents 8-18 years. CONCLUSIONS: LSG is a safe and - in the short term - effective bariatric procedure for adolescent obesity (follow up 24 months). Long-term results with larger numbers of patients and involving additional features, such as quantification of VAT and HF as markers of metabolic risk and insulin resistance, are warranted to further understand the effectiveness and safety and to further explore the long-term benefits of this procedure in adolescence.

Operative management of idiopathic spinal intradural arachnoid cysts in children: a systematic review.

BACKGROUND: Spinal intradural arachnoid cysts are rare with only a few patients reported so far. Idiopathic, traumatic, posthemorrhagic, and postinflammatory causes have been reported in the literature. Especially, idiopathic lesions, in which other possible etiological factors have been ruled out, seem to be rare. PATIENTS AND METHODS: We systematically reviewed the literature in regards to localization within the spinal canal, treatment options, complications, and outcome. Additionally, we present management strategies in two progressively symptomatic children less than 3 years of age with idiopathic intradural arachnoid cysts. RESULTS: In total, 21 pediatric cases including the presented cases have been analyzed. Anterior idiopathic spinal arachnoid cysts are predominantly located in the cervical spine in 87.5 % of all cases, whereas posterior cysts can be found at thoracic and thoracolumbar segments in 84.6 % of the patients. Most children presented with motor deficits (76.2 %). Twenty-five percent of anterior spinal arachnoid cysts caused back pain as the only presenting symptom. Open fenestration by a dorsal approach has been used in the vast majority of cases. No major surgical complications have been reported. Ninety-four percent of all patients did improve or showed no neurological deficits. Recurrence rate after successful surgical treatment was low (9.5 %). CONCLUSION: Idiopathic spinal intradural arachnoid cysts can present with neurological deficits in children. Pathologies are predominantly located in the cervical spine anteriorly and in thoracic and thoracolumbar segments posteriorly to the spinal cord. In symptomatic cases, microsurgical excision and cyst wall fenestration via laminotomy are recommended. Our radiological, intraoperative, and pathological findings support the cerebrospinal fluid obstruction and vent mechanism theory of arachnoid cysts.

A rare case of congenital choroid plexus carcinoma.

We report a 1-year-old child with the prenatal (week 29 + 5) diagnosis of a brain tumor. The parents were informed about all aspects of prognosis and options concerning termination of pregnancy. The parents opted for an aggressive therapeutic approach after extensive and informative case conferences and counseling. The histopathological diagnosis after partial tumor resection was choroid plexus carcinoma, two weeks thereafter tumor size was progressive. The parents opted for palliative treatment at this stage. The patient died at the age of one year. Ethical aspects have to be actively considered and addressed when caring for children with choroid plexus carcinoma.

Head Ultrasound and MR imaging in the evaluation of neonatal encephalopathy: competitive or complementary imaging studies?

Magnetic resonance (MR) imaging is superior to ultrasonography (US) for the evaluation and prognostication of neonates with neonatal encephalopathy (NE). Nonetheless, US may provide important information early in the course of NE and can be used to document the evolution of lesions. This article provides an overview of useful findings in the US evaluation of infants with NE. Although many of the findings do not appear as conspicuous or as extensively as they do on MR imaging, recognition and familiarity with subtle head US abnormalities may allow head US to play an important complementary role to MR imaging in the evaluation of infants with NE.

Acute cerebral infarction and extra pontine myelinolysis in children with new onset type 1 diabetes mellitus.

Neurological complications of diabetic ketoacidosis (DKA) are still associated with significant mortality and morbidity. We report on two children who suffered from acute cerebral infarction (CI) and extra pontine myelinolysis (EPM) at onset of type 1 diabetes. Initially, clinical management had not been performed according to generally accepted guidelines. Putative risk factors that may have predisposed for the development of acute cerebrovascular complications are discussed. Not only cerebral edema (CE) but also other severe neurological complications such as CI should be suspected when neurological deterioration occurs during DKA. We conclude that not only an exceeded rehydration therapy but also a rapidly reduced serum osmolality due to an unbalanced rapid blood sugar decrease and serum sodium increase may have lead to the neurological disease. We propose that a reserved and well-defined rehydration strategy in the first 6 (-12) h of therapy is crucial for recovery and can reduce neurological complications of patients with DKA.

Pyogenic osteomyelitis of the vertebral arch in children.

Vertebral infection represents 2% to 4% of all cases of osteomyelitis in children. Extension of vertebral osteomyelitis into the vertebral arch is rare; and exclusive pyogenic involvement is exceedingly rare, especially in children. A review of the literature revealed less than 25 combined cases, most of them reported in the beginning of the 20th century without cross-sectional imaging. The unusual location creates difficulties in distinguishing vertebral osteomyelitis from neoplasm and arthritic conditions. We present 2 cases of infection of the posterior vertebral elements. Most useful in identifying the presence and extent of infection were a sudden onset of nonspecific back pain, elevated inflammatory parameters, and magnetic resonance imaging. Antibiotic therapy with or without surgical intervention provided successful management. With the recurrence observed in 1 child, the most optimal treatment of this condition might still be unknown.

A yellowish subconjunctival lesion in an infant-congenital orbital fat herniation.

A very rare case of a congenital orbital fat herniation is demonstrated. Clinically, the child presented a progressive, small yellowish and mobile mass on the temporal orbital wall of her right eye. Magnetic resonance imaging showed a fat isointensive structure in T1-weighing without contrast enhancement. The possible aetiology of the herniation could be a congenital weakness of the Tenon's capsule or the conjunctival fornix.

Is sonography reliable for the diagnosis of pediatric blunt abdominal trauma?

BACKGROUND: Computerized tomography (CT) is considered as the imaging study of choice for blunt abdominal trauma in children. Nevertheless, recent investigations clearly indicate an increased risk of cancer in children exposed to radiation during abdominal spiral CT. Therefore, alternative strategies should be used for the diagnosis and surgical decision making in blunt abdominal trauma in children. METHODS: Retrospective analysis included all children with intraabdominal organ rupture after blunt abdominal trauma. Patients were diagnosed by a standardized emergency protocol that included primary clinical assessment and repeated ultrasound but not routine CT. Efficacy of abdominal ultrasound was evaluated in regard to safe diagnosis and appropriate surgical decision making. RESULTS: The study included 35 children with intraabdominal organ rupture diagnosed by ultrasound. One fifth (7/35) of the patients were polytraumatized, whereas 28 of 35 had an isolated blunt abdominal trauma. All patients underwent immediate ultrasound scanning of the abdomen and retroperitoneal space. Two patients were immediately operated because of hemodynamically instability. Four of 7 polytraumatized patients and 7 of 28 patients with isolated blunt abdominal trauma were additionally diagnosed by spiral CT. Only 1 patient underwent subsequent surgery because of the findings in the CT. Ultrasound was effective in more than 97% (34/35) of the patients for diagnosis and appropriate surgical decision making. CONCLUSION: Ultrasound combined with clinical assessment presents an effective method for safe diagnosis and appropriate surgical decision making in pediatric blunt abdominal trauma. Selected cases with polytrauma and/or unequivocal findings in the ultrasound should undergo abdominal CT. Patients requiring abdominal CT should have an anticipated benefit that exceeds the radiation risk. The importance of repeated clinical assessment cannot be overstated.

Mixed hepatoblastoma and teratoma of the liver in a 3-year-old child: a unique combination and clinical challenge.

Primary liver tumors in children are rare with malignant hepatoblastoma being the most common neoplasm. In this report, we describe the diagnosis and clinical management of a large liver tumor in a 3-year-old child that displayed the features of both, conventional hepatoblastoma and malignant teratoma. Pathological assessment on a pre-operative bioptical specimen showed an immature teratoid tumor with no area of hepatoblastic differentiation present. Histological and immunohistological examination of the resected tumor specimen additionally showed tumor areas of very different differentiation pattern intermixed with each other, namely areas of hepatoblastoma-typical and neuroblastoma-like morphology as well as areas of rhadomyosarcomatous differentiation.After chemotherapy the tumor size increased and an extended right hemihepatectomy was performed. Post-operatively, the general condition of the child improved and adjuvant chemotherapy was started two weeks later. 36 months after initial diagnosis the patient is healthy, in good general condition, and without any sign of residual tumor disease.Overall, we describe the diagnosis and clinical management of a large liver tumor in a 3-year-old child that displayed the features of both, conventional hepatoblastoma and malignant teratoma and was designated as mixed hepatoblastoma and teratoma. Though mesenchymal tumor portions can occur within hepatoblastomas, most commonly osteoid or chondroid, our case is different as it presents a large spectrum of mesenchymal and epithelial differentiation pattern in most of the lesion.

Pharmacokinetics and safety of gadobutrol-enhanced magnetic resonance imaging in pediatric patients.

OBJECTIVES: This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years. MATERIALS AND METHODS: In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2-6, 7-11, and 12-17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated. RESULTS: A total of 130 patients (2-6 years, n = 45; 7-11 years, n = 39; 12-17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 micromol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients. CONCLUSIONS: Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.