Arrested Hydrocephalus in Childhood: Case Series and Review of the Literature.

INTRODUCTION: Hydrocephalus can be progressive or spontaneously arrested. In arrested hydrocephalus, the balance between production and absorption of the cerebrospinal fluid is restored. Patients are mostly asymptomatic, and no surgical treatment is necessary for them. METHODS: We performed a two-center consecutive case series study, aimed at investigating the safety of nonsurgical management of hydrocephalus in selected pediatric patients. We retrospectively selected all consecutive patients, suspected to suffer from arrested hydrocephalus and referred to our two institutions between January 2011 and December 2013. Data on clinical and radiological follow-up were collected until June 2017. RESULTS: Five children diagnosed with arrested hydrocephalus were included in the study. All patients presented macrocephaly as the main presenting sign. Associated mild-to-moderate stable motor disorders were assessed in four out of five cases. Typical symptoms and signs associated with acute raised intracranial pressure were absent in all patients. Magnetic resonance imaging studies showed ventriculomegaly in all patients. A diagnosis of arrested hydrocephalus was made in all five cases based on stable clinical and radiological findings during the initial observation. Conservative management based on active surveillance was, therefore, proposed. During the follow-up period, we observed stable or improved conditions in four out of five patients, while the remaining patient presented progressive hydrocephalus. DISCUSSION: Making a distinction between arrested and progressive hydrocephalus is fundamental, because of the opposed appropriate management. Any newly discovered case of hydrocephalus, not characterized by clear signs of progressive hydrocephalus, should benefit from active surveillance before any definitive decision is taken.

Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

MR spectroscopy in children: protocols and pitfalls in non-tumorous brain pathology.

Proton nuclear magnetic resonance spectroscopy (MRS) delivers information about cell content and metabolism in a noninvasive manner. The diagnostic strength of MRS lies in its evaluation of pathologies in combination with conventional magnetic resonance imaging (MRI). MRS in children has been most widely used to evaluate brain conditions like tumors, infections, metabolic diseases or learning disabilities and especially in neonates with hypoxic-ischemic encephalopathy. This article reviews some basic theoretical considerations, routine procedures, protocols and pitfalls and will illustrate the range of spectrum alterations occurring in some non-tumorous pediatric brain pathologies.

Patient-specific spinal stiffness in AIS: a preoperative and noninvasive method.

INTRODUCTION: The clinical tests currently used to assess spinal biomechanics preoperatively are unable to assess true mechanical spinal stiffness. They rely on spinal displacement without considering the force required to deform a patient's spine. We propose a preoperative method for noninvasively quantifying the three-dimensional patient-specific stiffness of the spines of adolescent idiopathic scoliosis patients. METHODS: The technique combines a novel clinical test with numerical optimization of a finite element model of the patient's spine. RESULTS: A pilot study conducted on five patients showed that the model was able to provide accurate 3D reconstruction of the spine's midline and predict the spine's stiffness for each patient in flexion, bending, and rotation. Statistically significant variation of spinal stiffness was observed between the patients. CONCLUSION: This result confirms that spinal biomechanics is patient-specific, which should be taken into consideration to individualize surgical treatment.

Axial suspension test to assess pre-operative spinal flexibility in patients with adolescent idiopathic scoliosis.

INTRODUCTION: An accurate description of the biomechanical behavior of the spine is crucial for the planning of scoliotic surgical correction as well as for the understanding of degenerative spine disorders. The current clinical assessments of spinal mechanics such as side-bending or fulcrum-bending tests rely on the displacement of the spine observed during motion of the patient. Since these tests focused solely on the spinal kinematics without considering mechanical loads, no quantification of the mechanical flexibility of the spine can be provided. METHODS: A spinal suspension test (SST) has been developed to simultaneously monitor the force applied on the spine and the induced vertebral displacements. The system relies on cervical elevation of the patient and orthogonal radiographic images are used to measure the position of the vertebras. The system has been used to quantify the spinal flexibility on five AIS patients. RESULTS: Based on the SST, the overall spinal flexibility varied between 0.3 °/Nm for the patient with the stiffer curve and 2 °/Nm for the less rigid curve. A linear correlation was observed between the overall spinal flexibility and the change in Cobb angle. In addition, the segmental flexibility calculated for five segments around the apex was 0.13 ± 0.07 °/Nm, which is similar to intra-operative stiffness measurements previously published. CONCLUSIONS: In summary, the SST seems suitable to provide pre-operative information on the complex functional behavior and stiffness of spinal segments under physiological loading conditions. Such tools will become increasingly important in the future due to the ever-increasing complexity of the surgical instrumentation and procedures.

Pyridoxal phosphate-responsive seizures in a patient with cerebral folate deficiency (CFD) and congenital deafness with labyrinthine aplasia, microtia and microdontia (LAMM).

We present an 8-year-old boy with folate receptor alpha (FRα) defect and congenital deafness with labyrinthine aplasia, microtia and microdontia (LAMM syndrome). Both conditions are exceptionally rare autosomal recessive inherited diseases mapped to 11q13. Our patient was found to have novel homozygous nonsense mutations in the FOLR1 gene (p.R204X), and FGF3 gene (p.C50X). While the FRα defect is a disorder of brain-specific folate transport accompanied with cerebral folate deficiency (CFD) causing progressive neurological symptoms, LAMM syndrome is a solely malformative condition, with normal physical growth and cognitive development. Our patient presented with congenital deafness, hypotonia, dysphygia and ataxia in early childhood. At the age of 6 years he developed intractable epilepsy, and deteriorated clinically with respiratory arrest and severe hypercapnea at the age of 8 years. In contrast to the previously published patients with a FOLR1 gene defect, our patient presented with an abnormal l-dopa metabolism in CSF and high 3-O-methyl-dopa. Upon oral treatment with folinic acid the boy regained consciousness while the epilepsy could be successfully managed only with additional pyridoxal 5'-phosphate (PLP). This report pinpoints the importance of CSF folate investigations in children with unexplained progressive neurological presentations, even if a malformative syndrome is obviously present, and suggests a trial with PLP in folinic acid-unresponsive seizures.

Neonatal brain infections.

Infections of the brain in the neonatal period differ considerably from infections in the older child, due to a variety of age-specific factors that are related not only to the child, but also to the mother, and to specific pathogenic organisms. It has been recognized that clinical and neurological signs are often non-specific, sometimes scarce, and seldom correlate with the extent of neuroimaging findings, thus warranting early imaging to ensure timely therapy and improved outcome.

Sclerema neonatorum after therapeutic whole-body hypothermia.

Hypothermia is being studied as a neuroprotective therapy after asphyxia. This report is about a term newborn with severe asphyxia who underwent systemic hypothermia (34.5 degrees C) for 72 h. He survived without apparent brain damage but developed sclerema on his back, in the area in contact with the cooling mattress. The sclerema resolved without scarring after three months.

Diffusion tensor imaging in cases of adrenoleukodystrophy: preliminary experience as a marker for early demyelination?

BACKGROUND AND PURPOSE: Diffusion tensor imaging measures the proton diffusivity and preferential orientation of the diffusion tensor. X-linked adrenoleukodystrophy is a demyelinating disease for which therapy depends on the onset and extension of demyelination. We investigated the ability of diffusion tensor imaging to detect changes in the demyelinated lesions and in the normal appearing white matter. METHODS: Diffusion tensor imaging of three related boys with X-linked adrenoleukodystrophy and seven age-matched control participants was performed. Isotropic diffusion (D') and fractional anisotropy (FA) values were determined in 18 regions of interest in the white matter of both hemispheres. RESULTS: In all the demyelinated white matter areas, a pattern with increased D' and loss of FA was found. For example, mean D' was 1.772 x 10(-3)mm(2)/s in patient 2 with blindness and extensive demyelination of the occipital white matter and was 0.693 x 10(-3)mm(2)/s in control participants (P =.01). In the same region, mean FA was 0.103 (0.464 in control participants, P <.0001). Significant alterations of D' and FA were also observed in normal appearing white matter. For example, mean D' was 0.802 x 10(-3)mm(2)/s in the parietal white matter of patient 1 with no visible alterations on T2-weighted images (0.715 x 10(-3) mm(2)/s in control patients, P =.03), whereas mean FA was 0.320 (0.400 in control participants, P =.003). CONCLUSION: Elevated D' and loss of FA revealed by diffusion tensor imaging are consistent with severe demyelination in patients with X-linked adrenoleukodystrophy. Significant alterations of D' and FA in normal appearing white matter may indicate early demyelination in areas that are not yet visibly altered on conventional MR images. Further evaluation in a larger series of patients and long-term study are needed.

Vanishing cerebellum in myelomeningocoele.

Reduced hindbrain herniation observed after intrauterine myelomeningocoele repair suggests that posterior fossa changes in myelomeningocoele are secondary results of prolonged prenatal spinal cerebrospinal fluid leak. Exceptionally, this transforaminal herniation results in 'degeneration' of cerebellar tissue, presumably due to mechanically induced ischaemia. This phenomenon was called 'vanishing cerebellum in Chiari II malformation'. We report three similar cases of this apparently rare finding. Pregnancies were normal. Cerebellar hypoplasia was already recognized in one instance by prenatal ultrasound at gestational week 25. Postnatal imaging was similar in all three patients showing small posterior fossa, beaked midbrain tectum, small brainstem without pontine prominence, reduced cerebellar tissue with virtual absence of one hemisphere and supratentorial hydrocephalus. Our series is too small to draw firm conclusions about predisposing risk factors for and consequences of vanishing cerebellum. Cerebellar damage can interfere with cognitive development, as shown in children with cerebellar agenesis/ hypoplasia, congenital ataxia and small cerebellum following prematurity. A final conclusion on the cognitive consequence of vanishing cerebellum cannot be drawn on the available literature and our limited observations, as one of our patients died at 3 months and another is still too young for appropriate testing. However, the third (aged 15 years) is very severely retarded.

Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel mutation in the LMNA gene.

Mutations in A-type nuclear lamins are known to cause a variety of diseases, which can affect almost all organs of the human body including striated muscle. For lamin-related congenital muscular dystrophy two different phenotypes are known to date. Here, we describe a 3-year-old, white Caucasian girl with a novel de novo mutation in the LMNA gene with marked hypotonia of neck and trunk muscles with dropped head posture, loss of cervical lordosis and marked joint laxity. In addition to this novel mutation, the patient also had cerebral white matter lesions on MRI and cognitive impairment on developmental testing. This is only the second A-type lamin-related congenital muscular dystrophy patient in which white matter lesions are described. Thus, white matter involvement might be a feature in A-type lamin-related congenital muscular dystrophy, warranting screening of these patients for both white matter lesions and cognitive impairment.

Skeletal muscle MRI of the lower limbs in congenital muscular dystrophy patients with novel POMT1 and POMT2 mutations.

Alpha-dystroglycanopathies form a genetically heterogeneous group of congenital muscular dystrophies with a large variety of clinical phenotypes. Within this group mutations in the protein O-mannosyltransferase genes (POMT1 and POMT2) are known to cause a spectrum of CMD disorders including the Walker-Warburg Syndrome with severe brain and ocular malformations, and the limb girdle muscular dystrophy with and without mental retardation. In this case report the clinical phenotype and brain and muscle MRI findings of two siblings of 10 and 7years (male/female) homozygous for a novel mutation in the POMT1 gene (c.2220G>C, p.Trp740Cys) and a 10year old boy with two novel mutations in the POMT2 gene ((c.215G>A, p.Arg72His) and (c.713G>T, p.Gly238Val) are presented. Mutation detection was performed by direct sequencing of the FKRP, FKTN, POMT1 and POMT2 genes. T1-weighted axial muscle MRI of the lower limbs revealed diffuse fatty degeneration of thigh and calf muscles with predominance of gluteus maximus, adductor magnus, posterior thigh, medial gastrocnemius, and peroneus muscles, but no edematous changes. As a similar pattern of muscle involvement had been described in FKRP related α-dystroglycanopathy LGMD2I, we conclude that α-dystroglycanopathies may present with distinctive muscle MRI changes.

Are vigabatrin induced T2 hyperintensities in cranial MRI associated with acute encephalopathy and extrapyramidal symptoms?

Reversible T2-hyperintensities in cranial MRI have been recently observed in infants with infantile spasms, who were treated with vigabatrin. In most cases, this phenomenon is solely been reported in neuroimaging practice without clinical relevance. We report two patients with infantile spasms, who not only developed transient T2-hyperintensities, but also presented acute encephalopathy, and extrapyramidal symptoms under vigabatrin therapy.

Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): a randomized controlled trial.

BACKGROUND: Antibiotics are overused in children and adolescents with lower respiratory tract infection (LRTI). Serum-procalcitonin (PCT) can be used to guide treatment when bacterial infection is suspected. Its role in pediatric LRTI is unclear. METHODS: Between 01/2009 and 02/2010 we randomized previously healthy patients 1 month to 18 years old presenting with LRTI to the emergency departments of two pediatric hospitals in Switzerland to receive antibiotics either according to a PCT guidance algorithm established for adult LRTI or standard care clinical guidelines. In intention-to-treat analyses, antibiotic prescribing rate, duration of antibiotic treatment, and number of days with impairment of daily activities within 14 days of randomization were compared between the two groups. RESULTS: In total 337 children, mean age 3.8 years (range 0.1-18), were included. Antibiotic prescribing rates were not significantly different in PCT guided patients compared to controls (OR 1.26; 95% CI 0.81, 1.95). Mean duration of antibiotic exposure was reduced from 6.3 to 4.5 days under PCT guidance (-1.8 days; 95% CI -3.1, -0.5; P = 0.039) for all LRTI and from 9.1 to 5.7 days for pneumonia (-3.4 days 95% CI -4.9, -1.7; P<0.001). There was no apparent difference in impairment of daily activities between PCT guided and control patients. CONCLUSION: PCT guidance reduced antibiotic exposure by reducing the duration of antibiotic treatment, while not affecting the antibiotic prescribing rate. The latter may be explained by the low baseline prescribing rate in Switzerland for pediatric LRTI and the choice of an inappropriately low PCT cut-off level for this population. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN17057980 http://www.controlled-trials.com/ISRCTN17057980.

Odontogenic myxoma: diagnostic and therapeutic challenges in paediatric and adult patients--a case series and review of the literature.

INTRODUCTION: Odontogenic myxomas are benign but locally invasive tumours originating from primordial mesenchymal tooth forming tissues which do not metastasise. We present a series of two paediatric and two adult cases and focus on differences in diagnostic and therapeutic approaches between children and adults based on our own experience and a critical review of the literature.

Panhypopituitarism presenting as life-threatening heart failure caused by an inherited microdeletion in 1q25 including LHX4.

Clinical presentation of hypopituitarism in the neonate may be variable, ranging from absent to severe nonspecific symptoms and may be life-threatening in patients with adrenocorticotropic hormone deficiency. The LIM homeobox gene 4 (LHX4) transcription factor regulates early embryonic development of the anterior pituitary gland. Autosomal dominant mutations in LHX4 cause congenital hypopituitarism with variable combined pituitary hormone deficiency (CPHD). We report on a neonate with unexplained heart failure and minor physical anomalies, suggesting a midline defect. She was diagnosed with complete CPHD. Cardiac function was rescued by replacement with hydrocortisone and thyroxine; hypoglycaemia stopped under growth hormone therapy. Magnetic resonance imaging revealed a dysgenetic pituitary gland suggesting an early developmental defect. Array comparative genomic hybridization showed a maternally inherited 1.5-megabase microdeletion in 1q25.2q25.3, including the LHX4 gene. Haploinsufficiency of LHX4 likely explains the predominant pituitary phenotype in the proposita and we suggest variable intrafamilial penetrance of the inherited microdeletion. To the best of our knowledge, we are the first to report on heart failure as a rare nonspecific symptom of treatable CPHD in the newborn. Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development.

MR imaging of neonatal brain infections.

Infections of the brain in the postnatal period differ from those in older children as a result of a combination of distinct epidemiologic factors in general, and immaturity of neonatal brain and immunologic host response in particular. It has been recognized that clinical and neurologic signs are often nonspecific, sometimes scarce, and seldom correlate with the extent of neuroimaging findings, thus warranting an early MR imaging examination in the course of the disease, enabling rapid therapy institution and better clinical outcome. This article reviews most of postnatal pathogen agents involved in neonatal brain infections, related physiopathology, and neuroimaging findings.

Maturation of the limbic system revealed by MR FLAIR imaging.

BACKGROUND: Cortical signal intensity (SI) of the limbic system in adults is known to be higher than in neocortical structures, but time-related changes in SI during childhood have not been described. OBJECTIVE: To detect maturation-related SI changes within the limbic system using a fluid-attenuated inversion recovery (FLAIR) MR sequence. MATERIALS AND METHODS: Twenty children (10 boys, 10 girls; age 3.5-18 years, mean 11.2 years) with no neurological abnormality and normal MR imaging examination were retrospectively selected. On two coronal FLAIR slices, ten regions of interest (ROI) with a constant area of 10 mm2 were manually placed in the archeocortex (hippocampus), periarcheocortex (parahippocampal gyrus, subcallosal area, cingulate gyrus) and in the neocortex at the level of the superior frontal gyrus on both sides. RESULTS: Significant SI gradients were observed with a higher intensity in the archeocortex, intermediate intensity in the periarcheocortex and low intensity in the neocortex. Significant higher SI values in hippocampal and parahippocampal structures were detected in children up to 10 years of age. CONCLUSION: These differences mainly reflected differences in cortical structure and myelination state. Archeocortical structures especially showed significant age-related intensity progression suggesting ongoing organization and/or myelination until early adolescence.