Quality Requirements for the early Fetal Ultrasound Assessment at 11-13+6 Weeks of Gestation (DEGUM Levels II and III).

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. OBJECTIVE: To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. METHODS: Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. RESULTS: MOG antibodies (median 1:2560; range 1:160-1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). CONCLUSIONS: Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα). This genetic defect gives rise to a progressive neurological disorder with late infantile onset. We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy. We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy. We found four novel pathogenic alleles, one splice mutation and three missense mutations. Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid. These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations. Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients. Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency.

Life with too much polyprenol: polyprenol reductase deficiency.

Congenital disorders of glycosylation (CDG) are caused by a dysfunction of glycosylation, an essential step in the manufacturing process of glycoproteins. This paper focuses on a 6-year-old patient with a new type of CDG-I caused by a defect of the steroid 5α reductase type 3 gene (SRD5A3). The clinical features were psychomotor retardation, pathological nystagmus, slight muscular hypotonia and microcephaly. SRD5A3 was recently identified encoding the polyprenol reductase, an enzyme catalyzing the final step of the biosynthesis of dolichol, which is required for the assembly of the glycans needed for N-glycosylation. Although an early homozygous stop-codon (c.57G>A [W19X]) with no functional protein was found in the patient, about 70% of transferrin (Tf) was correctly glycosylated. Quantification of dolichol and unreduced polyprenol in the patient's fibroblasts demonstrated a high polyprenol/dolichol ratio with normal amounts of dolichol, indicating that high polyprenol levels might compete with dolichol for the initiation of N-glycan assembly but without supporting normal glycosylation and that there must be an alternative pathway for dolichol biosynthesis.

Long-term outcome of children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) is characterized by cerebellar symptoms and magnetic resonance imaging (MRI) changes primarily confined to the cerebellum. OBJECTIVE: To analyze the neurological and cognitive long-term outcome of children with AC. METHODS: Children with AC diagnosed by typical clinical features and MRI findings were included in this retrospective study. Medical charts were reviewed and neurological deficits were assessed by neurological examination or by the expanded disability status scale telephone interview. Cognitive outcome was evaluated with a parental questionnaire (Kognitive Probleme bei Kindern und Jugendlichen). RESULTS: A total of 11 children (6 boys, 5 girls; age range: 3 years to 14 years and 10 months) were included. Of them, six children had a severe disease manifestation including mental status changes and neurological symptoms. Of the rest, two children had a moderate and three children had a mild form of AC. MRI of the cerebellum was obtained in the acute phase revealing signal alterations with different patterns. The average follow-up period was 4 years and 4 months. A complete recovery was observed in five children. Neurological sequelae were reported in five children ranging from ataxia to mild tremor. Cognitive deficits were found in six patients. The affected areas of cognition did include spatial visualization ability, language skills, and concentration. CONCLUSION: Neurological and cognitive sequelae are common in children with AC and underline the role of the cerebellum in cognition.

Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) may be implicated in the immunopathogenesis of multiple sclerosis (MS) inducing demyelination in the animal model of MS. In adults reported anti-MOG antibody frequencies have been variable across a number of studies and can also be detected in controls. OBJECTIVE: To measure antibodies against MOG in paediatric patients with demyelinating disorders of the central nervous system and in controls. METHODS: Serum antibodies against MOG and myelin basic protein were measured by ELISA, flow cytometry (FACS) and in the liquid phase in 11 children with acute disseminated encephalomyelitis (ADEM), 22 children with MS, seven children with acute viral encephalitis and 13 healthy controls. The serostatus of Epstein-Barr virus (EBV) infections were assessed. RESULTS: Anti-MOG antibodies, measured either by ELISA or FACS were exclusively detected in children with demyelination. In ADEM these antibodies were highly reactive. Anti-MBP reactivity was detectable equally in all groups. The presence of either autoantibodies did not associate with EBV serostatus, age, gender or disease course. CONCLUSIONS: This study independently corroborates recently published results of seroprevalence and specificity of the assay. Due to their low sensitivity anti-MOG antibodies will not serve as disease-specific biomarkers, but could help to support the diagnosis of ADEM in difficult cases.

Expanding the spectrum of neurological disease associated with Epstein-Barr virus activity.

The purpose of this study was to delineate the spectrum of neurological diseases attributed to Epstein-Barr virus (EBV) activity. The approach was a retrospective study on patients with EBV activity proven by a positive EBV antibody-specific index (AI) and/or cerebrospinal fluid (CSF) PCR. One hundred six children and adults (AI positive = 77, AI + PCR positive = 3, PCR positive = 26) were identified, most with reactivated infections. Twenty-eight showed typical EBV-related diseases (encephalitis, neuritis, meningitis), 19 further infections (HSV encephalitis, neuroborreliosis, HIV infection, bacterial meningitis), nine immune-mediated disorders (multiple sclerosis, optic neuritis), and 50 further diseases not typical for EBV. The highest AI values occurred in patients with encephalitis. No relationship between disease category or AI values and viral loads was found. Additional reanalysis of 1,500 consecutive CSF EBV PCR studies revealed the highest positive rates among patients with further infections (n = 18/227, 7.9%) but lower rates among patients with typical EBV-related disorders (5/395; 1.3%), immune-mediated disorders (n = 2/174; 1.1%) and other conditions (n = 4/704; 0.6%). Intrathecal EBV activity is not restricted to typical EBV-related disorders, unexpectedly frequent in further CNS infections and also present in non-inflammatory conditions. Prospective studies should assess the pathogenic role of EBV in these different diseases.

Epilepsy with myoclonic absences - favourable response to add-on rufinamide treatment in 3 cases.

BACKGROUND: Epilepsy with myoclonic absences (EMA) is a rare epileptic syndrome with frequently poor response to antiepileptic treatment. Rufinamide (RUF) is a relatively new EMEA- and FDA-approved anticonvulsant licensed as an orphan drug for the adjunctive treatment of patients with Lennox-Gastaut syndrome. METHODS: A retrospective data analysis in 3 patients was performed. RESULTS: Add-on RUF treatment was initiated in 3 boys with EMA refractory to conventional antiepileptic therapy (primidone + valproic acid, n=1; levetiracetame + ethosuximide, n=2). It resulted in complete cessation of all seizures in 2, and a 50% reduction of the seizure frequency in one child, respectively. CONCLUSIONS: RUF add-on therapy should be considered in children with EMA not responding to conventional antiepileptic therapy.

Impact of herpes simplex virus detection in respiratory specimens of patients with suspected viral pneumonia.

BACKGROUND: Respiratory infection and failure is a commonly encountered problem in intensive care unit (ICU) patients. However, despite the accumulating body of evidence to suggest that herpes simplex virus type 1 (HSV-1) is associated with pneumonia, the exact role played by this virus in this process is still not fully understood. Therefore, to identify patients at risk, we have conducted a case-control study to characterize patients with HSV-1-positive pneumonia. PATIENTS AND METHODS: Between 2007 and 2009, all patients with suspected viral pneumonia were tested for the presence of herpes viruses using a PCR assay approach with respiratory specimens. To identify possible associations, risk factors, and impact of HSV, HSV-1-positive ICU patients (n = 51) were compared to age-, gender-, and department- and season-matched HSV-negative patients (n = 52). RESULTS: HSV-positive patients differed significantly from the HSV-negative ones only in terms of time of mechanical ventilation (13 vs. 6 days, respectively; p = 0.002). Subgroup analysis in the patients aged >60 years and in those without bacterial detection revealed a similar trend (p = 0.01 and p = 0.004, respectively). Mortality did not differ between the groups or between the HSV-1-positive patients treated with aciclovir and those who were not. A viral load >10E+05 geq/ml was associated with mechanical ventilation (20/21 vs. 17/29; p = 0.004), acute respiratory distress syndrome (ARDS; 19/21 vs. 18/29; p = 0.005), sepsis (18/21 vs. 14/29; p = 0.008), detection of a bacterial pathogen in the same specimen (10/21 vs. 4/29; p = 0.01) and longer ICU stay (25 vs. 30 days; p = 0.04). CONCLUSION: Despite several associations with high viral load, the clinical outcome of HSV-1-positive ICU patients did not differ significantly from the clinical outcome of HSV-negative patients. This finding indicates that HSV-1 viral loads in respiratory specimens are a symptom of a clinically poor condition rather than a cause of it. Longitudinal and therapy studies are therefore needed to distinguish between HSV-1 as a causative pathogen and HSV-1 as a bystander of pneumonia/ARDS.

Becker's muscular dystrophy aggravating facioscapulohumeral muscular dystrophy--double trouble as an explanation for an atypical phenotype.

We report a 12-year-old patient with mental impairment and proximal muscle weakness who had marked involvement of the shoulder girdle and facial muscles. CK levels were above 7000 U/l, multiplex PCR dystrophin gene deletion screening was negative. Further molecular studies revealed shortened D4Z4 fragments in the patient and his asymptomatic father, establishing the diagnosis of facioscapulohumeral muscular dystrophy (FSHD). Under the assumption of a second disease mechanism, a muscle biopsy was performed which revealed marked dystrophin deficiency. Eventually, a donor splice site mutation (c.4071+1 G>T) was found by direct sequencing of the dystrophin gene in the patient and his mother and confirmed the diagnosis of Becker's muscular dystrophy along with FSHD.

Obstruction of cerebral venous sinus secondary to idiopathic intracranial hypertension.

BACKGROUND: Whether cerebral venous sinus obstruction is a cause or consequence of idiopathic intracranial hypertension (IIH) is uncertain. METHODS AND RESULTS: Among the nine children with IIH, five showed stenosis (n = 5) and occlusion (n = 1) of cerebral venous sinus on cranial magnetic resonance imaging (n = 4) or conventional angiography (n = 1), respectively. Follow-up magnetic resonance imaging performed in four children showed complete regression of the venous pathology in one and partial regression in two of them. CONCLUSIONS: Our data demonstrate that cerebral venous sinus obstruction is frequent and frequently transient in pediatric IIH and suggest that stenoses may result from elevated intracranial pressure.

Severe speech delay as the presenting symptom of guanidinoacetate methyltransferase deficiency.

Guanidinoacetate methyltransferase deficiency typically presents with muscular hypotonia, global developmental delay, extrapyramidal signs, and seizures during infancy and childhood. The authors report a 5-year-old child with guanidinoacetate methyltransferase deficiency who presented with severe speech delay, emphasizing the importance of an early screening for disorders of creatine synthesis and transport in every infant or child with isolated speech delay of unknown cause.

Preclinical comparison in AR4-2J tumor-bearing mice of four radiolabeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-somatostatin analogs for tumor diagnosis and internal radiotherapy.

Somatostatin analogs labeled with radionuclides are of considerable interest in nuclear oncology as diagnostic or therapeutic tools for somatostatin receptor (SSTR)-expressing tumors. We investigated the suitability of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) as a replacement for the widely used diethylenetriaminepentaacetic acid, to enable stable labeling of somatostatin analogs with both therapeutic (90Y) and diagnostic (111In) radionuclides. The three clinically relevant somatostatin agonists, octreotide, vapreotide, and lanreotide, together with the newly designed Tyr3-octreotide (TyrOc), were conjugated to DOTA and labeled with 90Y or 111In. For all DOTA-somatostatin analogs tested, irrespective of the incorporated radionuclide, we observed favorable biodistribution profiles in AR4-2J tumor-bearing mice: 1) a rapid clearance from all SSTR-negative tissues except kidney; 2) a specific uptake in SSTR-positive tissues, including tumor; and 3) an excellent tumor penetration. The main route of excretion was via the kidneys. Nevertheless, DOTATOC was clearly superior to the other DOTA-somatostatin analogs tested, as well as OctreoScan, as indicated by the highest tumor-to-nontarget-tissue ratio, including the tumor-to-SSTR-positive-tissue ratios. The presence of different SSTR subtypes in the SSTR-positive tissues possibly contributes to these differential uptakes. We assume that the very favorable behavior of DOTATOC in our mouse model makes this radioligand very promising for future applications in nuclear oncology.

The extracellular matrix: an early target of preservation/reperfusion injury and acute rejection after small bowel transplantation.

BACKGROUND: Endothelial cells are known to be an early target of preservation/reperfusion injury and acute rejection, whereas the extracellular matrix (ECM) may also play an equally important role in the sequelae of both events. METHODS: Syngeneic and allogeneic rat small bowel transplantations (SBTX) were performed after 6 hr of preservation. Animals were subsequently killed at defined time points for determination of ECM parameters within the graft and in plasma. RESULTS: Laminin levels were significantly increased 20 min after reperfusion (syngeneic SBTX: 357+/-65.9 ng/ml; allogeneic SBTX: 361+/-79.6 ng/ml; P< or =0.01). After syngeneic transplantation, laminin levels normalized by postoperative day (POD) 7, whereas there was a rejection-induced increase after allogeneic SBTX (POD 7: 179+/-60.1 ng/ml; POD 9: 333+/-13.6 ng/ml; P< or =0.01 vs. syngeneic SBTX). This increase was accompanied by an increase in tumor necrosis factor-alpha levels at POD 9. Hyaluronic acid levels were significantly elevated after 24 hr (syngeneic SBTX: 1086+/-176 microg/L; allogeneic SBTX: 918+/-108 microg/L; P< or =0.01). After syngeneic SBTX, hyaluronic acid levels normalized by POD 7, whereas persistently higher levels were observed after allogeneic SBTX. Immunohistochemistry confirmed early changes (20 min after reperfusion) at the ECM. Anti-laminin and anti-CD44 staining normalized at POD 5 after syngeneic SBTX. After allogeneic SBTX, rejection-specific changes were evident with anti-laminin staining commencing on POD 5 and progressing until POD 9. At similar time points, increased expression of fibronectin- and interferon-gamma-positive material was evident. CONCLUSIONS: The ECM can be considered to be an early target of preservation/reperfusion injury and acute rejection. Plasma parameters reliably reflected the changes observed within the graft. Laminin and hyaluronic acid levels may be used as indicators of initial graft function. Furthermore, the increase in laminin levels was an early indicator of acute rejection. Determination of these parameters may significantly improve monitoring after SBTX.

Effects of prolonged partial liquid ventilation, high frequency ventilation and conventional ventilation on gas exchange and lung pathology in newborn surfactant-depleted piglets.

Partial liquid ventilation (PLV) improves oxygenation in various animal models of respiratory insufficiency. The aim of this study was to compare the effects of conventional ventilation (CV), high frequency oscillatory ventilation (HFOV), and PLV combined with CV or HFOV on gas exchange and histopathology. Thirty anaesthetised newborn piglets (mean weight 1.94 kg, age 1-3 days) were randomized in five groups of six animals: CV, CV + surfactant (S), HFOV+S, PLV/CV, and PLV/HFOV. Thirty min after lung injury had been induced with repeated saline lavage, specific ventilatory treatment was initiated. Three animals of the CV group died within the 24 h study period, whereas none died in any of the other groups. The oxygenation index (OI) and the PaO2/FIO2 ratio improved significantly within 30 min in all groups, but not in the CV group. After 24 h all oxygenation parameters were better in the PLV groups than in CV or CV+S (P < 0.05). No differences in gas exchange were noted between HFOV+S and PLV/CV. The combination of PLV with HFOV led to an increased PaO2/FIO2 ratio when compared with PLV/CV and with HFOV+S (P < 0.05). All PLV treated animals had significantly less lung injury in the upper and lower lobes compared with gas-ventilated animals by histologic semi-quantitative lung injury score (P < 0.01) and in the lower lobes by morphometry (P < 0.001). In conclusion, HFOV+S and PLV either with CV or HFOV are effective techniques to provide adequate gas exchange in S-deficient lungs compared with CV with and without S. However, lung injury was significantly improved in both PLV treated groups compared with HFOV+S and the CV groups.

Partial liquid ventilation with surfactant: effects on gas exchange and lung pathology in surfactant-depleted piglets.

OBJECTIVE: To evaluate the effects of 24 h partial liquid ventilation (PLV) with and without surfactant (S) treatment on gas exchange and lung injury in a newborn animal model of S deficiency. DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: Research laboratory in a university setting. SUBJECTS: Twenty-four pathogen-free, male piglets (mean weight 1.9 kg, age 1-3 days). INTERVENTIONS: The animals were randomised in four groups: PLV with FC-77 combined with conventional ventilation (PLV/CV) versus S + PLV/CV and PLV combined with high frequency oscillatory ventilation (PLV/HFOV) versus S + PLV/HFOV. The piglets were anaesthetised, intubated and instrumented with vascular catheters. Thirty minutes after lung injury had been induced with repeated saline lavage, S animals received natural S. Thirty minutes after surfactant substitution PLV with FC-77 was started. The oxygenation index (OI), PaO(2)/FIO(2) ratio, PaCO(2) and the ventilatory efficacy index were determined before and during PLV. After 24 h the lungs were removed for histopathological examination. MEASUREMENTS AND MAIN RESULTS: Within 60 min after the initiation of PLV, all animals demonstrated improvements of the OI and PaO(2)/FIO(2) ratio compared to the values after lung injury. However, at 18 and 24 h of PLV, the OI and PaO(2)/FIO(2) ratio were significantly worse in the S + PLV/CV and S + PLV/HFOV groups compared to the groups without S. PaCO(2) was higher at 18 and 24 h when S was used in PLV/HFOV (p < 0.05). A semi-quantitative lung injury score revealed most severe lung damage in the S + PLV/HFOV group. CONCLUSIONS++: The combination of S and PLV with FC-77 led to an impaired gas exchange and did not further protect the animal from lung injury.

Encephalitis related to primary varicella-zoster virus infection in immunocompetent children.

INTRODUCTION: Encephalitis is a rare complication of primary varicella-zoster virus (VZV) infection in immunocompetent children. METHODS: The clinical and laboratory findings of two girls with VZV-related encephalitis are reported. RESULTS: Both children presented with focal epileptic seizures, corresponding to cortical/subcortical as well as white matter lesions. The first showed a typical vesicular skin rash. She was easily diagnosed and made a rapid recovery during acyclovir and steroid treatment. In the second girl, a preceding measles-mumps-rubella virus vaccination and the absence of skin vesicles were misleading with respect to the diagnosis, which was finally proven by IgG seroconversion and intrathecal synthesis of IgG antibodies to VZV. She developed left parieto-occipital tissue necrosis and recovered only transiently during initial acyclovir/steroid treatment. Eight weeks after onset, progressive white matter demyelination and the occurrence of erythema nodosum in the lower limbs necessitated a second 4-month course of oral steroids. The VZV PCR from cerebrospinal fluid was negative in both children. CONCLUSIONS: Primary VZV infection may cause severe encephalitis that may occur without skin vesicles and lead to a chronic course with systemic vasculitis. The coincidence of vaccination and neurologic diseases offers no proof per se of a causal relationship.

Pneumonectomy in cystic fibrosis.

A 17-year-old boy and a 12-year-old girl with cystic fibrosis (forced expiratory volume in 1 sec, 36% and 14% of predicted values, respectively) developed severe right-sided lung infections with abscess formations and complete atelectases unresponsive to medical therapy. In both patients, unilateral emergency pneumonectomy resulted in rapid clinical improvement. Despite her severe underlying lung disease, the girl experienced a remarkable increase in quality of life; 2 years after surgery, she died from respiratory failure. The male patient has now survived for 4 years, and lung transplantation still remains a therapeutic option for him. We believe that pneumonectomy is a valuable rescue therapy for patients with cystic fibrosis and intractable unilateral lung infections who are at high risk of dying while waiting for lung transplantation.