Novelty in hypertension in children and adolescents: focus on hypertension during the first year of life, use and interpretation of ambulatory blood pressure monitoring, role of physical activity in prevention and treatment, simple carbohydrates and uric acid as risk factors.

The present article intends to provide an update of the article "Focus on prevention, diagnosis and treatment of hypertension in children and adolescents" published in 2013 (Spagnolo et al., Ital J Pediatr 39:20, 2013) in this journal. This revision is justified by the fact that during the last years there have been several new scientific contributions to the problem of hypertension in pediatric age and during adolescence. Nevertheless, for what regards some aspects of the previous article, the newly acquired information did not require substantial changes to what was already published, both from a cultural and from a clinical point of view. We felt, however, the necessity to rewrite and/or to extend other parts in the light of the most recent scientific publications. More specifically, we updated and extended the chapters on the diagnosis and management of hypertension in newborns and unweaned babies, on the use and interpretation of ambulatory blood pressure monitoring, and on the usefulness of and indications for physical activity. Furthermore, we added an entirely new section on the role that simple carbohydrates (fructose in particular) and uric acid may play in the pathogenesis of hypertension in pediatric age.

Focus on prevention, diagnosis and treatment of hypertension in children and adolescents.

The European Society of Hypertension has recently published its recommendations on prevention, diagnosis and treatment of high blood pressure in children and adolescents. Taking this contribution as a starting point the Study Group of Hypertension of the Italian Society of Pediatrics together with the Italian Society of Hypertension has conducted a reappraisal of the most recent literature on this subject. The present review does not claim to be an exhaustive description of hypertension in the pediatric population but intends to provide Pediatricians with practical and updated indications in order to guide them in this often unappreciated problem. This document pays particular attention to the primary hypertension which represents a growing problem in children and adolescents. Subjects at elevated risk of hypertension are those overweight, with low birth weight and presenting a family history of hypertension. However, also children who do not present these risk factors may have elevated blood pressure levels. In pediatric age diagnosis of hypertension or high normal blood pressure is made with repeated office blood pressure measurements that show values exceeding the reference values. Blood pressure should be monitored at least once a year with adequate methods and instrumentation and the observed values have to be interpreted according to the most updated nomograms that are adjusted for children's gender, age and height. Currently other available methods such as ambulatory blood pressure monitoring and home blood pressure measurement are not yet adequately validated for use as diagnostic instruments. To diagnose primary hypertension it is necessary to exclude secondary forms. The probability of facing a secondary form of hypertension is inversely proportional to the child's age and directly proportional to blood pressure levels. Medical history, clinical data and blood tests may guide the differential diagnosis of primary versus secondary forms. The prevention of high blood pressure is based on correct lifestyle and nutrition, starting from childhood age. The treatment of primary hypertension in children is almost exclusively dietary/behavioral and includes: a) reduction of overweight whenever present b) reduction of dietary sodium intake c) increase in physical activity. Pharmacological therapy will be needed rarely and only in specific cases.

Basal and post-ischemic vascular compliance in children/adolescents born small for gestational age.

BACKGROUND: Intrauterine growth restriction plays a powerful role in influencing later susceptibility to certain chronic diseases, such as hypertension. Endothelial dysfunction and arterial stiffness are early events in the development of cardiovascular diseases (CVDs). We have studied vascular compliance in small for gestational age (SGA) children/adolescents in comparison with that in appropriate for gestational age (AGA) subjects. METHODS: We monitored blood pressure, vascular resistance and compliance in 82 children-adolescents (52 SGA, 30 AGA), by means of pulse wave analysis (CR 2000 HDI) at the radial level, before and after 3 min of ischemic stress at the brachial level. RESULTS: In the children/adolescents born SGA we found a significant increase in systolic and diastolic blood pressure and vascular resistance in the basal condition; the large and small vessels were stiffer. After ischemia we observed an increased vascular response in the SGA children/adolescents: there was a great diminution of systolic and diastolic blood pressure and a larger increase of the elasticity of the conduit and resistance vessels. CONCLUSIONS: These data show that the SGA group presented some early signs of arterial wall functional disorders. More pediatric data are needed for the evaluation by non-invasive techniques of vascular function in children-adolescents at risk of CVD.

Silent increase of urinary ethylmalonic acid is an indicator of nonspecific brain dysfunction.

Our aim was to compare urinary ethylmalonic acid (EMA) levels in subjects who had no apparent clinical reason to have increased levels of this substance but were suffering from non-specific CNS impairment, and healthy controls. Urinary EMA concentrations detected by (1)H-NMR spectroscopy were studied in 130 subjects with CNS impairment of unknown origin (with no definite diagnosis, no specific symptoms or signs, and normal common biochemical and metabolic screening results) and 130 age- and sex-matched healthy subjects. EMA levels exceeding two standard deviations (SD) above normal (i.e. 8.1 mmol/molCn) were found in a subgroup of CNS-impaired patients and healthy controls. EMA levels exceeding 2 SD above normal were fourfold prevalent in the urine of patients with non-specific CNS impairment compared to from the EMA levels in healthy controls. Moreover, we found that the level exceeding > 8.1 mmol/molCn (i.e. > + 2 SD) had sufficient discrimination accuracy in identifying subjects with non-specific CNS impairment; the level exceeding 12 mmol/molCn (i.e. > + 6 SD) reaches suitable accuracy (i.e. 100% specificity and 78.6% sensitivity). These observations are of importance, as we found that subtle increases in urinary EMA levels are frequent in patients with non-specific CNS impairment. The reasons for this association remain unknown.

Activin A in asphyxiated full-term newborns with hypoxic ischemic encephalopathy.

Activin-A is a protein over-expressed and secreted by the brain after neuronal destruction. We evaluated whether serum activin-A increases in asphyxiated full-term newborns (AFTNs) at risk of hypoxic-ischemic-encephalopathy (HIE). 105 consecutive infants (35 affected by perinatal asphyxia due to acute fetal distress; 70 healthy gestational-age matched newborns) underwent cranial assessment and neurologic examination at 12, 24 and 72 hours after birth and, on discharge from the hospital and; activin-A and monitoring laboratory variables assessment at birth. According to the occurrence of HIE within 7-days after birth, AFTNs were subdivided in Group A (n= 20; no/mild HIE with good prognosis) and Group B (n= 15; moderate/severe HIE with a greater risk of neurological handicap). Activin-A was significantly (P less than 0.0001) higher in Groups A and B than controls and highest (P less than 0.001) in Group B. At 0.66 ng/L activin-A achieved a sensitivity of 93.33 per cent and a specificity of 96.63 per cent, respectively, as HIE diagnostic test. These findings show that activin A increased in AFTNs with HIE before the appearance of related signs.

[(1)H] magnetic resonance spectroscopy of urine: diagnosis of a guanidinoacetate methyl transferase deficiency case.

For the first time, the use of urine [(1)H] magnetic resonance spectroscopy has allowed the detection of 1 case of guanidinoacetate methyl transferase in a database sample of 1500 pediatric patients with a diagnosis of central nervous system impairment of unknown origin. The urine [(1)H] magnetic resonance spectroscopy of a 9-year-old child, having severe epilepsy and nonprogressive mental and motor retardation with no apparent cause, revealed a possible guanidinoacetic acid increase. The definitive assignment of guanidinoacetic acid was checked by addition of pure substance to the urine sample and by measuring [(1)H]-[(1)H] correlation spectroscopy. Diagnosis of guanidinoacetate methyl transferase deficiency was further confirmed by liquid chromatography-mass spectrometry, brain [(1)H] magnetic resonance spectroscopy, and mutational analysis of the guanidinoacetate methyl transferase gene. The replacement therapy was promptly started and, after 1 year, the child was seizure free. We conclude that for this case, urine [(1)H] magnetic resonance spectroscopy screening was able to diagnose guanidinoacetate methyl transferase deficiency.

Drug-resistant epilepsy and epileptic phenotype-EEG association in MECP2 mutated Rett syndrome.

OBJECTIVE: To determine in MECP2-mutated Rett syndrome (RTT [MIM 312750]): (1) the prevalence of drug-resistant epilepsy (DRE); (2) whether the presence of DRE is related to the abnormal EEG patterns or to the particular MECP2 mutant genotype. METHODS: Retrospective survey of a large population of patients (n=154) evaluated between 1978 to 2007 (May) at the Child Psychiatry and Neurology Unit of Siena (Italy) with both clinical and genetic (i.e. MECP2 mutated) diagnoses of RTT. Some subjects were followed for up to 20 years. Among those, cases with epilepsy were first selected for study; within that group, cases with DRE were identified and studied. The association between clinical severity of their epilepsy and quantitative or qualitative scores of EEG severity was tested using rank coefficients (Spearman's rho values). The relationship between DRE and RTT genotype category (i.e. gene deletion, gene duplication, early truncating mutation, late truncating mutation, and missense mutation) or a specific MECP2 genotype was tested using the chi-square test. A p-value <0.05 (two sided) was considered to indicate statistical significance. RESULTS: Prevalence of DRE was 16% (i.e. 16 DRE out of 100 MECP2-mutated RTT epileptic patients). No significant relationship was found between clinical severity of DRE and quantitative (p=0.9190) or qualitative EEG scores (p=0.1511). In addition, no significant relationship was found between the DRE and the RTT genotype category (chi-square=1.147, DF=4, p=0.8867), or a specific MECP2 genotype (chi-square=30.958, DF=39, p=0.8173). CONCLUSIONS: Although RTT MECP2-mutated patients suffer from a serious and progressive encephalopathy, it is "epileptogenic" but not "DREgenic" as they have a decreased risk (16%) for DRE compared to the general epileptic population (DRE: 20-40%). The presence of DRE is not related to abnormal EEG findings or a particular MECP2 mutant genotype. SIGNIFICANCE: These observations could be of help in the practical management and family counseling.

A new phenotypical variant of intrauterine growth restriction?

OBJECTIVES: A link between intrauterine growth restriction and major adult-onset diseases has been reported. In this study we observed a series of hitherto-unrecognized clinical features in a population of children with intrauterine growth restriction. PATIENTS AND METHODS: A total of 77 Italian children (aged 9.45 +/- 2.08 years) with antenatally diagnosed intrauterine growth restriction and small-for-gestational-age birth, along with their parents, were examined. The children with intrauterine growth restriction and were small for gestational age were subdivided into 2 groups ("variant" versus control subjects) according to evidence of auricle morphology deviation from normal. The following variables were determined: (1) external ear auricle geometry; (2) function of the posterior communicating arteries of the circle of Willis, as assessed by transcranial Doppler ultrasonography; (3) articular mobility, as assessed by Beighton's 9-point scale; (4) skin softness; and (5) distortion product-evoked otoacoustic emissions. RESULTS: Intrauterine growth restriction-variant children (n = 27) showed a significant female predominance, a lower proportion of maternal pregnancy-induced hypertension/preeclampsia, and a higher head circumference as compared with intrauterine growth restriction control subjects. Mothers of small-for-gestational-age-variant children showed significantly different auricular geometry parameters as compared with the intrauterine growth restriction controls mothers. An excess of bilaterally nonfunctioning posterior communicating arteries was observed both in the children with the intrauterine growth restriction-variant phenotype and their mothers as compared with the control groups. Significantly increased proportions of joint hypermobility and skin softness were observed in the intrauterine growth restriction-variant children as compared with controls subjects. Children with the intrauterine growth restriction-variant phenotype and their mothers showed bilateral distortion product-evoked otoacoustic emissions notches versus none in the control subjects, with an associated reduction of the area under the curve in both the intrauterine growth restriction-variant children and their mothers. No significant differences between the variant and control groups regarding the fathers were observed. CONCLUSIONS: We propose that the observed phenotypical constellation may represent an unrecognized variant of intrauterine growth restriction.

Magnesium profile in autism.

The aim of the present study was to determine and compare plasma and erythrocyte concentrations of magnesium in 12 autistic children (10 boys, 2 girls), 17 children with other autistic spectrum disorders (14 boys, 3 girls), 5 girls with classic Rett syndrome, and 14 normal children (7 boys, 7 girls) of the same age. No differences in intracellular Mg were found between controls and pathological subjects; however, autistic children and children with other autistic spectrum disorders had significantly lower plasma concentrations of Mg than normal subjects (p=0.013 and p=0.02, respectively). Although our study population was small, we conclude that children with autistic spectrum disorders require special dietary management. If these cases are diagnosed at an early stage, they can be helped through diet.

Selenium status, birth weight, and breast-feeding: pattern in the first month.

Selenium (Se) is an essential nutritional element for humans. A low Se status has been documented in formula-fed small-for-gestational age (SGA) newborns in the first month of life. The aim of the study was to compare the nutritional selenium status in adequate-for-gestational age (AGA) and in SGA newborns in the first month of life in relation to feeding type. Se status was assessed by plasma and erythrocyte concentrations, determined by pulsed Zeeman effect-atomic absorption spectrophotometry. We studied 210 newborns divided in groups according to birth weight (129 AGA, 81 SGA ) and feeding type (breast milk, formula, mixed) in wk 1-4 of postnatal life. Erythrocyte Se levels are affected neither by feeding type nor by birth weight. Se plasmatic concentrations were lower in SGA than in AGA newborns. Significant differences in mean plasma concentrations were found between formula-fed and breast-fed (p=0.013) and between formula-fed and mixed-fed (p=0.006) SGA newborns. The difference was not significant in AGA neonates. Breast-fed SGA newborns consistently showed higher plasma Se concentrations than formula-fed newborns. Unless supplemented from birth, Se intake will be inadequate in bottle-fed SGA infants.

Combined treatment with vigabatrin and topiramate in West syndrome.

The clinical and electroencephalographic (EEG) response to combined therapy with vigabatrin and topiramate was evaluated in five patients ages 7 to 15 months affected by West syndrome in an open-label trial. Four patients had cryptogenic and one patient had symptomatic (tuberous sclerosis) West syndrome. In cryptogenic patients who failed to respond to pyridoxine, vigabatrin was titrated to 80 to 100 mg/kg. Because control of infantile spasms or an EEG improvement was not obtained with vigabatrin treatment, topiramate was added (3-3.8 mg/kg/day). In all patients, the combined therapy with topiramate and vigabatrin achieved a rapid and complete normalization of infantile spasms, and in three patients with cryptogenic West syndrome, the EEG also became normal. In only one patient, transient anorexia was observed. This drug combination led to rapid neurodevelopmental normalization in cryptogenic patients. The results are promising and justify more trials in larger numbers of children with West syndrome.

Vagus nerve stimulation for drug-resistant epilepsy in children and young adults.

We present our experience with the use of intermittent vagal nerve stimulation in 13 patients with medically intractable epilepsy. A surgical approach, with the exception of callosotomy, was impossible. The age range was 6-28 years (median 17 years). In all patients the epilepsy was severe and in six of them was symptomatic. Seven patients had Lennox-Gastaut syndrome, one epilepsy with myoclonic-astatic seizures, four localization-related and one symptomatic generalized epilepsy. The length of the follow-up averaged 22 months (range 8 months-3 years). Of the 13 patients, five (38.4%) had a 50% or more reduction in the number of seizures compared with preimplantation. Of these patients, one with a localization-related epilepsy had a 90% reduction as well as a significant improvement in alertness. Three patients showed no improvement with regard to the number of seizures but there was an improvement in alertness and, in one case in hyperactivity. Some seizure types responded better than others did: complex partial seizures with secondary generalization and atonic seizures. All our responsive patients improved in the first 2 months of VNS activation and only one case with further improvement was observed after this period. Considering the severity of the epilepsy the results can be considered satisfactory. We think that this treatment appears to be a safe adjunctive therapy for children and adults with medically and surgically intractable epilepsy.

Hemimegalencephaly in tuberous sclerosis complex.

The purpose of this case report is to describe the computed tomographic and magnetic resonance imaging findings of the brain of a 16-month-old girl with an uncommon association between hemimegalencephaly and tuberous sclerosis complex. When a large calcification is found within a hemimegalencephalic cerebral hemisphere, further investigation of a suspected associated tuberous sclerosis complex or another phakomatosis is required to determine pertinent treatment options and genetic counseling.