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.

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.

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.

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.

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.

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.

MRI of the lungs in children.

Lung diseases of children often need diagnostic imaging beyond X-ray. Although CT is considered the gold standard of lung imaging, MRI is sufficient to answer most of the questions raised. After all, the exposure to radiation caused by one CT examination corresponds to approximately the effective dose of 200 chest radiographs. What is MRI's potential in the lung today? In diseases with alveolar pathology, cardiac- and respiratory-triggered MRI examinations are roughly equivalent to CT examinations. Distinct interstitial processes are easily diagnosable using MRI. Early interstitial processes may be missed by MRI, but conventional plain films fail to recognize them just as often. For identification of lung metastases, CT is still used as the initial diagnostic measure. Subsequent therapy monitoring may then be carried out with the help of MRI. Small bullae and pulmonary emphysema at present pose a problem to MRI. On the other hand, MRI is reliable for follow-up examinations in inflammatory diseases or for imaging of complications, and the increased use of lung MRI as an alternative to chest CT may contribute immensely to reducing radiation exposure in children.

A prismatic case: A 31-year old man who did not miss his pituitary.

Combined pituitary hormone deficiency (CPHD) is a rare disorder resulting from impaired production of several pituitary hormones. This report describes the 30-year history of a patient who has apparently lived without a pituitary. The patient, born in 1976, experienced recurrent episodes of hypoglycaemia (as low as 2.9 mg/dl) in early childhood and showed elevated liver enzymes up to the age of two years without specific diagnosis. At the age of approximately 13 years, he first presented at our Department of Paediatric Endocrinology (University Hospital for Children and Adolescents, Leipzig) with signs of hypopituitarism and a height SDS of - 5.4, a high pitched voice and hypogenitalism. Endocrine testing confirmed panhypopituitarism (GH 1.3 ng/mL, LH 0.8 mU/mL, FSH 0.1 mU/ml, ACTH <1.0 pmol/l, TSH 1.0 mU/l) and substitution therapy was initiated. Magnetic resonance imaging (MRI) of the sella turcica showed a planar, hypoplastic and empty sella with pituitary stalk aplasia and ectopic neurohypophysis. Currently nearly 31 years of age, though taking his medication irregularly or not at all, he claims to be in good mental and physical condition irrespective of compliance or non compliance with substitution therapy. This case illustrates the importance of continued follow-up in patients with hypopituitarism and a systemic transferral of adolescents with CPHD to the care of adult endocrinologists.

Assessment of pulmonary air trapping and obstruction in expiration: an experimental MRI study.

PURPOSE: The aim of this experimental study was to evaluate the potential of a simple expiration technique by means of magnetic resonance imaging (MRI) in an animal model to detect pulmonary air-trapping areas after artificial bronchial obstruction. MATERIAL AND METHODS: Sixteen pigs were evaluated by means of a modified T1-weighted FLASH with fat saturation in respiratory arrest (TR=4.6 ms, TE=1.8 ms, alpha=10 degrees, S.D.=3-5 mm). A measurement of the signal intensity (SI) in the peripheral lung tissue was made in both inspiration and expiration before and after inhalation of 2 ml of 0.5% acetylcholine to simulate a bronchial obstruction. A final measurement of the lung SI was also made after bronchospasmolytic induction through salbutamol (beta2-mimetic bronchodilator). RESULTS: In expiration, a mean SI increase in peripheral lung tissue of about 183% was seen in comparison to inspiration (mean SI increase of 11-32). After inhalation of 0.5% acetylcholine, the expirational signal increase in peripheral lung tissue was only 114% of the original SI. The expirational signal homogeneity decreased after inhalation of acetylcholine. After inhalation of salbutamol, the lung tissue signal elevation in expiration was 193%. CONCLUSION: We interpret the low expiratory signal elevation after acetylcholine inhalation as a result of an air-trapped bronchial constriction in certain areas. The simple expiratory technique in an animal model showed that it is suitable to demonstrate obstructive air trapping using MRI.

MR Imaging-guided percutaneous procedures in children.

Magnetic resonance imaging (MRI)-guided therapeutic interventions in children are very rare. In comparison to other imaging techniques, it is very unusual for MRI to be used for diagnostic percutaneous interventions despite its imaging benefits. We provide a brief description of available MRI systems and instruments and use clinical examples to present and discuss typical indications for percutaneous procedures while showing possibilities for percutaneous therapeutic interventions.

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.

PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis.

Mutations in the PROP1 gene are the most frequent genetic defects in patients with combined pituitary hormone insufficiency. However, controversy exists about the timing and extent of pituitary insufficiency, and it remains unclear whether adrenal failure is a typical feature of this condition. We performed a retrospective longitudinal analysis of nine patients with PROP1 mutations who were under medical supervision at our clinic for 15.7 +/- 3.4 yr. All patients initially presented with growth failure (height sd score, -3.7 +/- 0.3) at a mean age of 4.9 +/- 0.8 yr. They were first diagnosed with GH and TSH deficiency, and replacement therapy was instituted at 6.1 +/- 1.1 and 6.8 +/- 1.2 yr, respectively. All seven patients who reached pubertal age required sex hormone substitution at 15.0 +/- 0.7 yr. Repeated functional testing of the anterior pituitary axes revealed a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH. All patients developed at least partial adrenal insufficiency, with a gradual decline of the function of the pituitary adrenal axis and eventually required substitution with hydrocortisone at a mean age of 18.4 +/- 3.5 yr. It is concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.

Pulmonary resorption of inhaled gadobutrol in an animal model: usage to determine lung diffusion in MRI examinations.

The aim of this study was to examine a pulmonary gadobutrol resorption after inhalation. An examination of 16 young swine, which were given different amounts of gadobutrol through inhalation, was performed. A measurement of the signal elevation in peripheral lung tissue as well as in the thoracic aorta was made using a T(1)-weighted FLASH-3D sequence in a 1.5 T magnetic resonance imaging (MRI) machine. Twenty minutes after gadobutrol application, a steep signal elevation in the aorta was reported, as well as a plateau phase after 45 min. The signal elevation in peripheral lung tissue after inhalation increased to a mean of 33.9%. The concurrent signal elevation of the abdominal aorta was 137.4%. The evaluation of an intravascular signal elevation after gadobutrol inhalation opens the possibility to evaluate and obtain lung diffusion with MRI.

Magnetic resonance angiography in a patient with Crohn's disease associated cerebral vasculitis.

Vasculitits of the central nervous system (CNS) is a known complication of chronic inflammatory bowel diseases. We report the case of a female patient with Crohn's disease, developing vasculitis of the CNS with evidence of pathological vessel depiction on magnetic resonance angiography. To our knowledge this is the first case report regarding MRA documentation of vessel changes typical for angiitis in a patient with Crohn-associated vasculitis of the CNS.

Microadenomas of the pituitary gland in children with and without hypophyseal dysfunction in magnetic resonance imaging.

The aim of this study was to correlate lesions of the pituitary gland with hormonal dysregulation. The hormonal status of 63 children was correlated with MRI findings of the pituitary gland. Two radiologists judged the MRI examinations without knowledge of the hormonal situation. The reliability of the diagnosis "adenoma" was evaluated in five steps from 0-100% for each sequence. A microadenoma was found in six of 14 children with hyperprolactinemia and in six of eight patients with increased IGF-I/IGFBP-3. However, microadenomas were also detected in eight of 28 children without hormonal dysfunction (clinical feature: obesity). The adenomas were seen best in a dynamic sequence after gadolinium administration. An expansive growing macroadenoma was found in one of 13 patients with hypopituitarism. We found a relatively high number of microadenomas even in children without any hormonal dysfunction. Taking into account the reported autopsy results (6.1-27% occult microadenomas), we suggest that the MRI diagnosis "microadenoma" is made too frequently if usual MRI criteria are used. Patients with increased levels of IGF-I/IGFBP-3 had a high incidence of microadenoma (up to 87.5%). Hyperprolactinemia was associated with microadenomas in about 43% (-57%) of patients (nearly on the same level as children without hormonal dysfunction). Therefore unspecific stimulation of the pituitary gland with consecutive increased volume seems to be responsible for hyperprolactinemia in many of these patients.

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.

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.