Predictive value of the General Movements Assessment and Standardized Infant NeuroDevelopmental Assessment in infants at high risk of neurodevelopmental disorders.

AIM: To compare the predictive values of the General Movements Assessment (GMA) and the Standardized Infant NeuroDevelopmental Assessment (SINDA) neurological scale for atypical neurodevelopmental outcome in 3-month-old at-risk infants. METHOD: A total of 109 infants (gestational age 30 weeks; range: 24-41; 52 males) attending a non-academic outpatient clinic were assessed with the GMA and the SINDA at 3 (2-4) months corrected age. The GMA pays attention to the complexity of general movements and presence of fidgety movements. Atypical neurodevelopmental outcome at 24 months corrected age (and older) implied cerebral palsy (CP) or a Bayley Mental Development Index or Bayley Psychomotor Development Index lower than 70. RESULTS: At 24 months corrected (and older) age, 16 children had an atypical outcome, including 14 children with CP. Regarding markedly reduced general movement complexity in combination with absent or sporadic fidgety movements, the GMA predicted an atypical outcome with specificity, positive, and negative predictive values greater than 0.900, and sensitivity of 0.687 (95% confidence interval [CI] = 0.460-0.915). SINDA predicted an atypical outcome with sensitivity, specificity, and negative predictive value greater than 0.900 and a positive predictive value of 0.652 (95% CI = 0.457-0.847). Regarding absent fidgety movements only or markedly reduced general movement complexity, the GMA predicted the outcome less well than both general movement criteria. INTERPRETATION: The SINDA and GMA both predict neurodevelopmental outcome well, but SINDA is easier to learn than the GMA; being a non-video-based assessment, it allows caregiver feedback during the consultation whereas the GMA usually does not.

Correlates of perceived shared decision making with parents of children with special healthcare needs: Findings from the PART-CHILD study.

OBJECTIVE: To assess the extent of perceived shared decision making (SDM) with parents of pediatric patients and to examine its association with characteristics of patients, professionals, and healthcare facilities. METHODS: Parents of pediatric patients (n = 4383) were recruited in 15 social pediatric centers in Germany and provided information on perceived SDM (binary CollaboRATEpediatric score: optimal versus suboptimal extent of SDM), child age and sex, type of impairment, appointment, and healthcare professional present at the appointment. Organizational characteristics were assessed in a cross-sectional survey of staff at the study sites. RESULTS: Overall, 58.4% of parents reported an optimal extent of SDM. The optimal extent of SDM was more likely reported by parents of girls (OR=1.27, p < 0.001) and children with physical (as opposed to cognitive and combined) impairments (OR=1.30, p = 0.006), and after appointments attended by allied health professionals (OR=1.28, p = 0.004). In addition, parents in facilities receiving financing in addition to compensation by statutory health insurance funds were less likely to report an optimal extent of perceived SDM. CONCLUSION: While SDM with parents was mostly related to individual characteristics of children and professionals at appointments, organizational characteristics seemed less relevant in our study. PRACTICE IMPLICATIONS: Staff should be made aware of lower SDM with parents of boys, older children, and those with cognitive impairments, and trained to improve the SDM in these groups.

Evaluation of a Complex Intervention to Strengthen Participation-Centred Care for Children with Special Healthcare Needs: Protocol of the Stepped Wedge Cluster Randomised PART-CHILD Trial.

INTRODUCTION: Participation is an important dimension of healthy child development and is associated with higher self-rated health, educational attainment and civic engagement. Many children with special healthcare needs (SHCN) experience limited participation and are thus at risk for adverse health and developmental outcomes. Despite this, interventions that promote participation in healthcare are scarce. We therefore evaluate the effectiveness of a complex age- and condition-generic intervention that strengthens participation-centred care involving parents and their children with SHCN by, inter alia, assessing preferences, specifying participation goals and facilitating shared decision-making in care. METHODS AND ANALYSIS: In this study protocol we describe the design and procedures for an unblinded, stepped wedge, cluster randomised trial conducted in 15 German interdisciplinary healthcare facilities providing services for children aged 0-18 years with SHCN. Sites are randomised to five periods in which they switch from control to intervention condition in blocks of three. The intervention includes: (1) team training focused on participation-centred care, (2) introduction of a new software facilitating participation-focused documentation and (3) implementation support promoting the transfer of training content into routine care. Study sites deliver routine care while in the control condition. As primary outcome, the degree of perceived shared decision-making with parents (CollaboRATEpediatric parent scale), a potential antecedent of achieving participation goals in everyday life, is assessed on one randomly selected day per week during the entire study period, directly following care appointments. We aim to sample 70 parents per study site and period. Additionally, participation of children is assessed within a closed embedded cohort with three parent and patient surveys. Intervention effectiveness will be modelled with a marginal model for correlated binary outcomes using generalised estimation equations and complete cases. A comprehensive mixed-methods process evaluation complements the effectiveness analyses.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Standardized Infant NeuroDevelopmental Assessment developmental and socio-emotional scales: reliability and predictive value in an at-risk population.

AIM: To assess the reliability and predictive validity of the developmental and socio-emotional scales of the Standardized Infant NeuroDevelopmental Assessment (SINDA). METHOD: To assess reliability, two sets of three assessors forming eight assessor-pairs independently rated the developmental and socio-emotional scales of 60 infants. To evaluate predictive validity, 223 infants (gestational age 30wks [range 23-41wks]; 117 males, 106 females) attending a non-academic outpatient clinic were assessed by different assessors with SINDA's neurological, developmental, and socio-emotional scales. Atypical neurodevelopmental outcome at a corrected age of 24 months or older implied a Bayley Mental or Psychomotor Developmental Index score of less than 70 or neurological disorder (including cerebral palsy). Behavioural and emotional disorders were classified according to the International Classification of Diseases, 10th Revision. Predictive values were calculated from SINDA (2-12mo corrected age, median 7mo) and typical versus atypical outcome, and for intellectual disability only (Mental Developmental Index <70). RESULTS: Assessors highly agreed on the developmental and socio-emotional assessments (developmental scores: Spearman's rank correlation coefficient ρ=0.972; single socio-emotional behaviour items: Cohen's κ=0.783-0.896). At 24 months or older, 65 children had atypical outcome. Atypical neurological scores predicted atypical outcome (sensitivity 83%, specificity 96%); atypical developmental scores predicted intellectual disability (sensitivity 77%, specificity 92%). Atypical emotionality and atypical self-regulation were associated with behavioural and emotional disorders. INTERPRETATION: SINDA's three scales are reliable, and have a satisfactory predictive validity for atypical developmental outcome at 24 months or older in a non-academic outpatient setting. SINDA's developmental scale has promising predictive validity for intellectual disability. SINDA's socio-emotional scale is a tool for caregiver counselling. WHAT THIS PAPER ADDS: Standardized Infant NeuroDevelopmental Assessment (SINDA)'s developmental and socio-emotional scales have excellent interrater reliability. Replication of the satisfactory validity of SINDA's neurological scale for atypical outcome.

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

OBJECTIVE: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations. METHODS: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies. RESULTS: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix. INTERPRETATION: Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

Measuring social participation in children with chronic health conditions: validation and reference values of the child and adolescent scale of participation (CASP) in the German context.

BACKGROUND: While ICF-CY-based models of care are promising avenues for improving participation of children with chronic health conditions, feasible and valid instruments to assess participation as an outcome in routine are still needed. We aimed to validate a German parent-report version of the Child and Adolescent Scale of Participation (CASP) in children with chronic health conditions of different severity. METHODS: Cross-sectional data were collected in 327 children (mean age 7.8 years, 55% boys) from two paediatric centres (n = 112) and one population-based sample (n = 215). Cronbach's alpha, factor analyses, face validity assessments, correlation analyses, receiver operating characteristics (ROC) curves, and parent-reported health-related quality of life (HRQoL: KINDL) were used to examine internal consistency, test-retest reliability, and capacity to differentiate between disease severity groups. Disease severity was operationalized according to ICD-diagnosis groups and/or parent-reports on health problems, medical and educational support, and medication. A newly developed item "overall perceived participation" was added to the CASP and evaluated. RESULTS: We found good to excellent content validity, excellent internal consistency, and good-to-excellent test-retest reliability of the instrument. While children with mild disease had a significantly greater extent of participation (higher CASP scores) than children with severe disease, they did not differ from healthy children. Children with mild compared to severe disease much more differed in participation as measured by the CASP compared to the KINDL (area under the ROC curve: 0.92 vs. 0.75). In addition, the item "overall perceived participation" was highly correlated (r = 0.86) with the CASP total score, indicating the potential value of this specific single item. Finally, we provided preliminary reference values for the CASP obtained in a population-based sample of children without chronic health conditions. CONCLUSIONS: The German version of the CASP and the new item are efficient, valid and reliable measures of social participation in childhood. The CASP-measured participation focuses more on attendance than on involvement into social circumstances of everyday life. To detect children with a high burden of disease on everyday life, the CASP may be more accurate than HRQoL instruments such as the KINDL. As outcome measurement, the CASP may facilitate the implementation of patient-centred paediatric health care.

Quality of life and correlating factors in children, adolescents with epilepsy, and their caregivers: A cross-sectional multicenter study from Germany.

PURPOSE: To identify factors correlating with poorer quality of life (QoL) in children and adolescents with epilepsy and regarding QoL and depression of their caregivers in Germany. METHOD: A cross-sectional multicenter study on QoL and depression was performed in two representative German states (Hessen and Schleswig-Holstein). Variance analysis, linear regression, and bivariate correlation were used to identify correlating factors for poorer QoL and symptoms of depression. RESULTS: Data from 489 children and adolescents (mean age 10.4 ± 4.2 years, range 0.5-17.8; 54.0% male) and their caregivers were collected. We identified missing seizure freedom (p = 0.046), concomitant diseases (p = 0.007), hospitalization (p = 0.049), recent status epilepticus (p = 0.035), living in a nursing home or with foster parents (p = 0.049), and relevant degree of disability (p = 0.007) to correlate with poorer QoL in children and adolescents with epilepsy. Poorer QoL of caregivers was associated with longer disease duration (p = 0.004), non-idiopathic (mainly structural-metabolic) epilepsy (p = 0.003), ongoing seizures (p = 0.003), concomitant diseases (p = 0.003), relevant disability (p = 0.003), or status epilepticus (p = 0.003) as well as with unemployment of the primary caretaker (p = 0.010). Symptoms of depression of caregivers were associated with non-idiopathic epilepsy (p = 0.003), concomitant diseases (p = 0.003), missing seizure freedom (p = 0.007), status epilepticus (p = 0.004), or a relevant disability (p = 0.004) of their ward. A poorer QoL value of the children and adolescents correlated with a poorer QoL value of the caregivers (p < 0.001). CONCLUSIONS: Epilepsy shows a considerable impact on QoL and symptoms of depression. Early and effective therapy should focus on reduction of seizure frequency and the probability for developing status epilepticus. Furthermore, comprehensive care should pay attention at comorbidities, consequences of disability and dependency on others.

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.

OBJECTIVE: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants. METHODS: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed. RESULTS: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified. CONCLUSIONS: This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Reliability and predictive validity of the Standardized Infant NeuroDevelopmental Assessment neurological scale.

AIM: To assess reliability and predictive validity of the neurological scale of the Standardized Infant NeuroDevelopmental Assessment (SINDA), a recently developed assessment for infants aged 6 weeks to 12 months. METHOD: To assess reliability, three assessors independently rated video-recorded neurological assessments of 24 infants twice. Item difficulty and discrimination were determined. To evaluate predictive validity, 181 infants (median gestational age 30wks [range 22-41wks]; 92 males, 89 females) attending a non-academic outpatient clinic were assessed with SINDA's neurological scale (28 dichotomized items). Atypical neurodevelopmental outcome at 24 months or older corrected age implied a Bayley Mental Developmental Index or Psychomotor Developmental Index lower than 70 or a diagnosis of cerebral palsy (CP). Predictive values were calculated from SINDA (2-12mo corrected age, median 3mo) and typical versus atypical outcome. RESULTS: Intraclass correlation coefficients of intrarater and interrater agreement of the neurological score varied between 0.923 and 0.965. Item difficulty and discrimination were satisfactory. At 24 months or older, 56 children (31%) had an atypical outcome (29 had CP). Atypical neurological scores (below 25th centile, ≤21) predicted atypical outcome and CP with sensitivities of 89% and 100%, and specificities of 94% and 81% respectively. INTERPRETATION: SINDA's neurological scale is reliable and in a non-academic outpatient setting has a satisfactory predictive validity for atypical developmental outcome, including CP, at 24 months or older. WHAT THIS PAPER ADDS: The Standardized Infant NeuroDevelopmental Assessment's neurological scale has a good to excellent reliability. The scale has promising predictive validity for cerebral palsy. The scale has promising predictive validity for other types of atypical developmental outcome.

CONFIABILIDAD Y VALIDEZ PREDICTIVA DE LA ESCALA NEUROLÓGICA DE LA EVALUACIÓN DEL NEURODESARROLLO INFANTIL ESTANDARIZADA: OBJETIVO: Evaluar la confiabilidad y la validez predictiva de la escala neurológica de la Evaluación del Neurodesarrollo Infantil Estandarizada (SINDA), una evaluación desarrollada recientemente para bebés de 6 semanas a 12 meses. MÉTODO: Para evaluar la confiabilidad, tres evaluadores evaluaron dos veces, de forma independiente, las evaluaciones neurológicas grabadas en videos de 24 recién nacidos. Se determinaron la dificultad del ítem y la discriminación. Para evaluar la validez predictiva, se evaluaron 181 neonatos (mediana de edad gestacional de 30 semanas [rango 22-41 semanas], 92 varones, 89 mujeres) que asisten a una clínica ambulatoria no académica con la escala neurológica de SINDA (28 ítems dicotomizados). El resultado del desarrollo neurológico atípico a los 24 meses o mayor edad corregida implicaba un índice de desarrollo mental o índice de desarrollo psicomotor Bayley inferior a 70 o un diagnóstico de parálisis cerebral (PC). Los valores predictivos se calcularon a partir de SINDA (edad corregida 2-12mo, mediana 3meses) y resultado típico versus a atípico. RESULTADOS: Los coeficientes de correlación intraclase de la concordancia intra e inter codificador del puntaje neurológico variaron entre 0.923 y 0.965. La dificultad del item y la discriminación fueron satisfactorias. A los 24 meses o más, 56 niños (31%) tuvieron un resultado atípico (29 tuvieron PC). Las puntuaciones neurológicas atípicas (por debajo del percentil 25, ≤21) predijeron un resultado atípico y PC con sensibilidades del 89% y del 100%, y especificidades del 94% y del 81%, respectivamente. INTERPRETACIÓN: La escala neurológica de SINDA es confiable y en un entorno ambulatorio no académico tiene una validez predictiva satisfactoria para la detección del desarrollo atípico, incluido la PC, a los 24 meses o más.

CONFIABILIDADE E VALIDADE PREDITIVA DA ESCALA NEUROLÓGICA DE AVALIAÇÃO PADRONIZADA NEURODESENVOLVIMENTAL INFANTIL: OBJETIVO: Avaliar a confiabilidade e validade preditiva da escala neurológica Avaliação Padronizada Neurodesenvolvimental Infantil (SINDA), uma avaliação desenvolvida recentemente para lactentes de 6 semanas a 12 meses de idade. MÉTODO: Para avaliar a confiabilidade, por duas vezes três avaliadores pontuaram independentemente avaliações neurológicas de 24 lactentes registradas em vídeo. Para avaliar a validade preditiva, 181 lactentes (idade gestacional mediana de 30 semanas[variação de 22 a 41 semanas]); 92 do sexo masculino; 89 do sexo feminino) que frequentavam uma clínica não acadêmica foram avaliados com a escala neurológica da SINDA (28 itens dicotomizados). O neurodesenvolvimento atípico na idade de 24 meses de idade corrigida ou mais tarde foi determinado por índice desenvolvimental mental da Bayley ou Item desenvolvimental psicomotor menor do que 70 ou diagnóstico de paralisia cerebral (PC). Os valores preditivos foram calculados para o SINDA (2-12 meses de idade corrigida, mediana de 3 m) e resultado típico versus atípico. RESULTADOS: Os coeficientes de correlação intraclasse de concordância intra ou inter-examinadores do escore neurológico variaram de 0,923 a 0,965. A dificuldade e discriminação do item foram satisfatórias. Aos 24 meses de idade ou mais, 56 crianças (31%) tiveram resultado atípico (29 tinham PC). Os escores neurológicos atípicos (abaixo do percentil 25, ≤21) foram preditivos de resultado atípico e PC com sensibilidades de 89% e 100%, e especificidades de 94% e 81%, respectivamente. INTERPRETAÇÃO: A escala neurológica SINDA é confiável e em um ambiente não acadêmico tem validade preditiva satisfatória para resultado atípico do desenvolvimento, incluindo PC, aos 24 meses de idade ou mais.

Vojta therapy and neurodevelopmental treatment in children with infantile postural asymmetry: a randomised controlled trial.

[Purpose] Physical therapy is an acknowledged and frequently applied method for infantile postural asymmetry. However, there is not yet sufficient evidence for its effectiveness. [Subjects and Methods] In a randomised controlled trial, the effect of Vojta therapy versus Neurodevelopmental treatment is assessed in infants with postural asymmetry. 65 infants with postural asymmetry were recruited. 37 infants aged six to eight weeks (mean 7.38) were found to be eligible and randomly assigned to two groups, with 19 receiving Vojta and 18 Neurodevelopmental treatment. Using a standardised and blinded video-based assessment, we documented restriction in head rotation and convexity of the spine in prone and supine position before and after therapy. A reduction of at least four points (range of scale 20 points) in postural asymmetry was regarded as a clinically relevant change. [Results] On average a four-point reduction was achieved in both groups within eight weeks. A mean difference (pre-post) between the groups of -2.96 points in favour of Vojta therapy was observed. [Conclusion] While both Neurodevelopmental treatment and Vojta are effective in the treatment of infantile postural asymmetry and comparably well applied by the parents, therapeutic effectiveness is significant greater within the Vojta group.

Predictive value of General Movement Assessment for preterm infants' development at 2 years - implementation in clinical routine in a non-academic setting.

BACKGROUND: General movements (GM) are used in academic settings to predict developmental outcome in infants born preterm. However, little is known about the implementation and predictive value of GM in non-academic settings. AIMS: The aim of this study is twofold: To document the implementation of GM assessment (GMA) in a non-academic setting and to assess its predictive value in infants born preterm. METHODS AND PROCEDURES: We documented the process of implementing GMA in a non-academic outpatient clinic. In addition, we assessed the predictive value of GMA at 1 and 3 months' corrected age for motor and cognitive development at 2 years in 122 children born <33 weeks' gestation. Outcome at two years was based upon the Bayley Scales of Infant Development-II (mental/psychomotor developmental index (MDI, PDI)) and a neurological examination. The infants' odds of atypical outcome (MDI or PDI ≤70 or diagnosis CP) and the predictive accuracy of abnormal GMA were calculated in a clinical routine scenario, which used all available GM information (primarily at 3 months or at 1 month, when 3 months were not available). In addition, separate analysis was undertaken for the samples of GMA at 1 and 3 months. OUTCOMES AND RESULTS: Tips to facilitate GMA implementation are described. In our clinical routine scenario, children with definitely abnormal GM were more likely to have an atypical two-year outcome than children with normal GM (OR 13.2 (95% CI 1.56; 112.5); sensitivity 55.6%, specificity 82.1%). Definitely abnormal GM were associated with reduced MDI (-12.0, 95% CI -23.2; -0.87) and identified all children with cerebral palsy (CP) in the sample of GMA at 3 months only. CONCLUSIONS AND IMPLICATIONS: GMA can be successfully implemented in a non-academic outpatient setting. In our clinical routine scenario, GMA allowed for adequate prediction of neurodevelopment in infants born preterm, thereby allaying concerns about diagnostic accuracy in non-academic settings.

Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life.

INTRODUCTION: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. METHODS: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. RESULTS: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. DISCUSSION: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.

Autoantibodies to neuronal antigens in children with focal epilepsy and no prima facie signs of encephalitis.

OBJECTIVE: There is increasing awareness of neuronal autoantibodies and their impact on the pathogenesis of epilepsy. We investigated children with focal epilepsy in order to provide an estimate of autoantibody frequency within a pediatric population without prima facie evidence of encephalitis using a broad panel of autoantibodies. This was done to assess the specificity of antibodies and to see whether antibodies might be of modifying influence on the course of focal epilepsies. METHOD: We searched for autoantibodies in 124 patients with focal epilepsy (1-18 years; mean 10; 6 years). Sera were tested using a broad panel of surface and intracellular antigens. RESULTS: We found autoantibodies in 5/124 patients (4%): high-positive GAD65 antibodies (n = 1), low-positive GAD65 antibodies (N = 1), VGKC complex antibodies not reactive with LGI1 or CASPR2 (n = 3). We did not find any distinctive features distinguishing antibody positive patients from those without antibodies. CONCLUSIONS: The antibodies found in this cohort are probably neither disease-specific nor pathogenic. This has been suggested before for these antigenic targets. Moreover, they do not seem to modify disease severity in the antibody-positive epilepsy patients.

[Parental Social Status and other determinants of quality of life and behavioral problems: An analysis of German preterm births between 1987-2004]. / Elterlicher Sozialstatus und andere Determinanten von Lebensqualität und Verhaltensauffälligkeiten : Eine Analyse deutscher Frühgeborener der Jahrgänge 1987-2004.

BACKGROUND: Knowledge of the factors affecting the development of preterm children in Germany is limited. We analysed the prevalence of preterm birth in Germany using the German Health Interview and Examination Survey for Children and Adolescents 2003-2006 and assessed factors associated with quality of life (QOL) and behavioural development in preterm children (< 37 weeks' gestational age). METHODS: Data were weighted and preterm prevalence was calculated by socioeconomic status (SES) and year of birth for 1,106 preterm children. Using linear regression models, the relationship between sociodemographic, pre- and perinatal, lifestyle, and contextual determinants on the one hand, and the QOL (KINDL® parent questionnaire) and behavioural problems (the total problem behaviour scale, the Strengths and Difficulties Questionnaire [SDQ]) on the other was calculated. RESULTS: Prevalence of preterm birth (mean 7.5 %) was higher in families with low compared with high SES (8.4 versus 7.0 %). In the final regression models, preterm children with high SES had higher QOL scores (+ 3.3 KINDL points, p = 0.024) compared with children with low SES, and adolescents (aged 14-17 years) had a higher QOL than children aged 7-13 years. All other variables (contextual, pre- and perinatal) were not related to QOL. In contrast, there were many determinants of behavioural development in preterms: the SDQ total score was lower in girls, children with older mothers, those from high SES and those with a high level of physical activity. However, both very low birth weight (< 1,500 g) and birth at > 34 weeks' gestation were associated with a higher SDQ total score. CONCLUSION: Given its high prevalence, preterm birth is a relevant public health issue in Germany. While SES may be the most important determinant of QOL in preterms, determinants of behavioural problems are the same as those in term children and also encompass perinatal factors.

LIS1-associated classic lissencephaly: A retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs.

BACKGROUND: Patients with LIS1-associated classic lissencephaly typically present with severe psychomotor retardation and drug-resistant epilepsy within the first year. AIM: To analyze the epileptogenic phenotype and response to antiepileptic therapy in LIS1-associated classic lissencephaly. METHOD: Retrospective evaluation of 22 patients (8 months-24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly in 16 study centers. RESULTS: All patients in our cohort developed drug-resistant epilepsy. In 82% onset of seizures was noted within the first six months of life, most frequently with infantile spasms. Later in infancy the epileptogentic phenotype became more variable and included different forms of focal seizures as well generalized as tonic-clonic seizures, with generalized tonic-clonic seizures being the predominant type. Lamotrigine and valproate were rated most successful with good or partial response rates in 88-100% of the patients. Both were evaluated significantly better than levetiracetam (p<0.05) and sulthiame (p<0.01) in the neuropediatric assessment and better than levetiracetam, sulthiame (p<0.05) and topiramate (p<0.01) in the family survey. Phenobarbital and vigabatrin achieved good or partial response in 62-83% of the patients. CONCLUSION: Our findings suggest that patients with LIS1-associated lissencephaly might benefit most from lamotrigine, valproate, vigabatrin or phenobarbital.

Costs of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany.

OBJECTIVE: To provide first data on the cost of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. METHODS: A population-based, cross-sectional sample of consecutive children and adolescents with epilepsy was evaluated in the states of Hessen and Schleswig-Holstein (total of 8.796 million inhabitants) in all health care sectors in 2011. Data on socioeconomic status, course of epilepsy, and direct and indirect costs were recorded using patient questionnaires. RESULTS: We collected data from 489 children and adolescents (mean age ± SD 10.4 ± 4.2 years, range 0.5-17.8 years; 264 [54.0%] male) who were treated by neuropediatricians (n = 253; 51.7%), at centers for social pediatrics ("Sozialpaediatrische Zentren," n = 110, 22.5%) and epilepsy centers (n = 126; 25.8%). Total direct costs summed up to €1,619 ± €4,375 per participant and 3-month period. Direct medical costs were due mainly to hospitalization (47.8%, €774 ± €3,595 per 3 months), anticonvulsants (13.2%, €213 ± €363), and ancillary treatment (9.1%, €147 ± €344). The total indirect costs amounted to €1,231 ± €2,830 in mothers and to €83 ± €593 in fathers; 17.4% (n = 85) of mothers and 0.6% (n = 3) of fathers reduced their working hours or quit work because of their child's epilepsy. Independent cost-driving factors were younger age, symptomatic cause, and polytherapy with anticonvulsants. Older age, active epilepsy, symptomatic cause, and polytherapy were independent predictors of higher antiepileptic drug (AED) costs, whereas younger age, longer epilepsy duration, symptomatic cause, disability, and parental depression were independent predictors for higher indirect costs. SIGNIFICANCE: Treatment of children and adolescents with epilepsy is associated with high direct costs due to frequent inpatient admissions and high indirect costs due to productivity losses in mothers. Direct costs are age-dependent and higher in patients with symptomatic epilepsy and polytherapy. Indirect costs are higher in the presence of a child's disability and parental depression.

Computer-based analysis of general movements reveals stereotypies predicting cerebral palsy.

AIM: To evaluate a kinematic paradigm of automatic general movements analysis in comparison to clinical assessment in 3-month-old infants and its prediction for neurodevelopmental outcome. METHOD: Preterm infants at high risk (n=49; 26 males, 23 females) and term infants at low risk (n=18; eight males, 10 females) of developmental impairment were recruited from hospitals around Heidelberg, Germany. Kinematic analysis of general movements by magnet tracking and clinical video-based assessment of general movements were performed at 3 months of age. Neurodevelopmental outcome was evaluated at 2 years. By comparing the general movements of small samples of children with and without cerebral palsy (CP), we developed a kinematic paradigm typical for infants at risk of developing CP. We tested the validity of this paradigm as a tool to predict CP and neurodevelopmental impairment. RESULTS: Clinical assessment correctly identified almost all infants with neurodevelopmental impairment including CP, but did not predict if the infant would be affected by CP or not. The kinematic analysis, in particular the stereotypy score of arm movements, was an excellent predictor of CP, whereas stereotyped repetitive movements of the legs predicted any neurodevelopmental impairment. INTERPRETATION: The automatic assessment of the stereotypy score by magnet tracking in 3-month-old spontaneously moving infants at high risk of developmental abnormalities allowed a valid detection of infants affected and unaffected by CP.