Varda Gross-Tsur

Convulsive status epilepticus in children

Summary: Status epilepticus (SE) occurs most commonly in infancy and childhood. Children with prior neurological abnormalities are most susceptible. More than 90% of cases are convulsive and the majority are generalized. SE may occur in the setting of an acute illness, in patients with established epilepsy or as a first unprovoked seizure. The etiology can be classified as idiopathic, remote symptomatic, febrile, acute symptomatic, or associated with a progressive encephalopathy. The morbidity and mortality of status have dramatically declined in recent years. Overall mortality in recent pediatric series was 3–10%, with almost all fatalities associated with acute central nervous system insults or progressive neurologic disorders. Neurological sequelae in children with idiopathic or febrile status are rare. Neurologically normal children with SE as their first unprovoked seizure have the same risk of experiencing subsequent seizures of any type as children who present with a brief first seizure. The risk of recurrent episodes of convulsive SE approaches 50% in neurologically abnormal children but is very low in neurologically normal children. The favorable outcome of SE in children may be related to advances in therapy and to the resistance of the immature brain to damage from seizures.

Protracted Clinical Course for Patientsd with Canavan Disease

Before the establishment of h‐acetylaspartic aciduria due to aspartoacylase deficiency as the cause of Canavan disease, diagnosis was based on the characteristic clinical features and spongiform encephalopathy, a pathological response shared by a number of other unrelated conditions. Thus confusion exists in the literature about the phenotype of spongiform encephalopathy (Canavan disease), with reports of juvenile and congenital forms, as well as the classical infantile type. In this report. six of 22 patients with infantile‐onset Canavan disease survived beyond six years of age. This phenotypical pattern might be the result of better medical management and care, rather than evidence of genetic heterogeneity.

The FSH-inhibin axis in prader-willi syndrome: heterogeneity of gonadal dysfunction

BackgroundWe characterized the spectrum and etiology of hypogonadism in a cohort of Prader-Willi syndrome (PWS) adolescents and adults.MethodsReproductive hormonal profiles and physical examination were performed on 19 males and 16 females ages 16–34u2009years with PWS. Gonadotropins, sex-steroids, inhibin B (INB) and anti-Mullerian hormone (AMH) were measured. We defined 4 groups according to the relative contribution of central and gonadal dysfunction based on FSH and INB levels: Group A: primary hypogonadism (FSH >15u2009IU/l and undetectable INB (<10u2009pg/ml); Group B: central hypogonadism (FSH <0.5u2009IU/l, INB <10u2009pg/ml); Group C: partial gonadal & central dysfunction (FSH 1.5–15u2009IU/l, INB >20u2009pg/ml); Group D: mild central and severe gonadal dysfunction (FSH 1.5–15u2009IU/l, INBu2009<u200910u2009pg/ml.ResultsThere were 10, 8, 9 and 8 individuals in Groups A-D respectively; significantly more males in group A (9, 4, 4 and 2; Pu2009=u20090.04). Significant differences between the groups were found in mean testosterone (Pu2009=u20090.04), AMH (Pu2009=u20090.003) and pubic hair (Pu2009=u20090.04) in males and mean LH (Pu2009=u20090.003) and breast development (Pu2009=u20090.04) in females. Mean age, height, weight, BMI and the distribution of genetic subtypes were similar within the groups.ConclusionsAnalysis of FSH and inhibin B revealed four distinct phenotypes ranging from primary gonadal to central hypogonadism. Primary gonadal dysfunction was common, while severe gonadotropin deficiency was rare. Longitudinal studies are needed to verify whether the individual phenotypes are consistent.

Prolonged febrile seizures, clinical characteristics, and acute management

Prolonged febrile seizures (PFS) lasting ≥15 min have been associated with increased risk for epilepsy in later life. Initial treatment, mostly prehospital, aims to prevent its evolution to febrile status epilepticus (FSE) and reduce adverse outcome. Paucity of information is available on the immediate treatment before reaching a hospital facility.

Epilepsy in Prader–Willi syndrome: experience of a national referral centre

The aim of the study was to characterize epilepsy, febrile seizures, electrographic features, and brain abnormalities in a large, national cohort of individuals with Prader–Willi syndrome (PWS).

Prader–Willi syndrome can be diagnosed prenatally

The aim of this study was to characterize the fetal phenotype of a cohort of individuals with confirmed diagnoses of Prader‐Willi syndrome (PWS), a severe multi‐system genetic disorder, diagnosed by a specific methylation test. We interviewed mothers of 106 individuals with PWS to obtain information about the pregnancy of their affected child. For 47 pregnancies of children younger than 10 years, we also reviewed the obstetric ultrasound and detailed obstetric history from medical records. We compared the PWS pregnancies with those of the sibling closest in age and with the general population. McNemars, Chi‐square and Fisher exact tests were used for statistical analyses. Decreased fetal movements, small for gestational age (SGA), asymmetrical intrauterine growth (increased head/abdomen circumferences ratio) and polyhydramnios were found in 88%, 65%, 43%, and 34%, respectively (Pu2009<u20090.001 vs. siblings and Pu2009<u20090.0001 vs. the general population for all measurements). No severe morphological abnormalities were found. A combination of 2, 3, and 4 abnormalities was found in 27%, 29%, and 24% of pregnancies, respectively. Fourteen out of 15 umbilical artery Doppler studies were within the normal range (93%). The rare combination of asymmetrical intrauterine growth and polyhydramnios was found in 34% of PWS pregnancies (Pu2009<u20090.0001 vs. the general population). Prenatal genetic screening for PWS by methylation testing is indicated when any combination of polyhydramnios, SGA or asymmetric intrauterine growth, with normal Doppler studies is present, particularly when asymmetrical intrauterine growth and polyhydramnios coexist.

Management of hypogonadism in adolescent girls and adult women with Prader-Willi syndrome.

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3u2009±u20097.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting‐center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20u2009ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual‐specific treatment; contraceptive pills, intra‐uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26‐year‐old woman with inhibin B and FSH levels 53u2009ng/ml and 6.4u2009IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult.

Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome

Context Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates “browning” of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS. Objectives Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids. Design and Study Participants A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls. Results Fasting glucose (77±9 vs 83±7mg/dl, p = 0.004), insulin (4.1±2.0 vs 7.9±4.7μU/ml, p<0.001), and triglycerides (74±34 vs 109±71mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79±0.041 vs 1.63±1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41±0.04 vs 0.36±0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5±52.0 vs 33.0±12.1ng/ml), plasma leptin (33.5±24.2 vs 19.7±19.3ng/ml) and plasma adinopectin (13.0±10.8 vs 7.6±4.5μg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041). Conclusions Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS.

Psychiatric disorders in a cohort of individuals with Prader–Willi syndrome

BACKGROUNDnPsychiatric manifestations in Prader-Willi Syndrome (PWS) are common and often are the most debilitating problem in these individuals. We present an epidemiological nation-wide survey of psychiatric diagnoses in the PWS population, based on full-range psychiatric interviews.nnnMETHODSnWe studied the distribution of psychiatric diagnoses (as opposed to a symptom-based approach) in the Israel national cohort of adolescents and adults with PWS. There was a total of 53 (32xa0males) ages 12xa0years and older. All individuals and their caretakers were interviewed using standardized psychiatric questionnaires. Demographic and clinical variables, Clinical Global Impression (CGI) score, IQ, severity of hyperphagia and quality of life (QOL) were also assessed and correlations with NPD (number of psychiatric diagnoses) calculated.nnnRESULTSnAn overwhelming majority (89%) of the study participants had at least one psychiatric diagnosis. The most common were disruptive behavior disorders (DBD) (68%), obsessive compulsive disorder (OCD) (45%) and skin picking (35%). Individuals with DBD were at increased risk for OCD and skin picking. Psychotic disorders were found in 11%. NPD had a significant negative influence on QOL. There was no correlation between NPD and BMI, IQ, hyperphagia severity, hormonal profile or genetic subtypes.nnnCONCLUSIONSnPsychiatric diagnoses are very frequent in PWS and strongly influence QOL. Furthermore, characterizing the profile of psychiatric comorbidity in PWS is crucial for planning effective interventions. Precise behavioral phenotyping in PWS in combination with a well-defined genetic etiology may aid biological research linking biological correlates to behavior.

Attitudes toward prenatal genetic testing and therapeutic termination of pregnancy among parents of offspring with Prader-Willi syndrome

INTRODUCTIONnPrenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility.nnnOBJECTIVEnTo explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus.nnnMETHODSnAll 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire.nnnRESULTSnFifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (pxa0<xa00.025), mothers education (pxa0<xa00.001), mothers work status (pxa0<xa00.001), current age of the child with PWS (pxa0<xa00.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age.nnnCONCLUSIONSnMost parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling.