A computational approach for detecting physiological homogeneity in the midst of genetic heterogeneity.

The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/ß immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.

From early motor ability to global cognitive development seven years after neonatal arterial ischemic stroke.

The developmental condition of children after neonatal arterial ischemic stroke (NAIS) is characterized by cognitive and motor impairments. We hypothesized that independent walking age would be a predictor of later global cognitive functioning in this population. Sixty-one children with an available independent walking age and full-scale IQ score seven years after NAIS were included in this study. Full-scale IQ was assessed using the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV). Independent walking age was negatively correlated with full-scale IQ score at seven years of age (Pearson correlation coefficient of -0.27; 95% confidence interval from 0.48 to -0.01; p <0.05). Early motor function is correlated with later global cognitive functioning in children after NAIS. Assessing and promoting early motor ability is essential in this population.

Perinatal inflammation exposure and developmental outcomes 7 years after neonatal arterial ischaemic stroke.

AIM: To test the association between perinatal inflammation exposure and Full-Scale IQ (FSIQ) score 7 years after neonatal arterial ischaemic stroke (NAIS). METHOD: We conducted a cross-sectional ancillary study nested in a multicentric longitudinal French cohort of infants born at term with NAIS between November 2003 and October 2006. Seventy-three children were included (45 males, 28 females). The a priori defined primary outcome measure was the FSIQ score assessed with the Wechsler Intelligence Scale for Children, Fourth Edition at 7 years of age. RESULTS: Seventeen (23%) of the included children were exposed to perinatal inflammation. Exposure to perinatal inflammation was independently associated with an increase of FSIQ score (coefficient 13.4, 95% confidence interval 1.3-25.4; p = 0.03). Children exposed to perinatal inflammation had a higher median cerebral volume, a lower median lesion volume, and less extensive lesion distributions compared to non-exposed children. INTERPRETATION: We propose the existence of two NAIS categories: arteritis-associated NAIS in children exposed to perinatal inflammation and embolism-associated NAIS in children non-exposed to perinatal inflammation. Identifying these two NAIS categories would open the possibility for specific curative strategies: anti-inflammatory strategy in arteritis-associated NAIS and recanalization strategy in embolism-associated NAIS.

Early Intensive Bimanual Stimulation Program (BB-Bim) for Infants at Risk of Unilateral Cerebral Palsy: A Randomized, Multiple-Baseline, Single-Case Study.

IMPORTANCE: Clinical practice guidelines for infants at high risk of cerebral palsy (CP) emphasize the importance of very early and intensive intervention. OBJECTIVE: To determine the feasibility of a new, home-based, early intensive bimanual stimulation program (BB-Bim) and its impact on hand function in infants at risk of unilateral CP. DESIGN: Single case experimental design, multiple baseline across subjects, lasting from 12 to 15 wk, including a 4- to 7-wk randomized baseline, followed by 8 wk of BB-Bim. SETTING: Home. PARTICIPANTS: Infants (ages 3-12 mo) with suspected unilateral CP, whose parents agreed to participate in the stimulation program. INTERVENTION: Parent-provided bimanual stimulation 20 min/day, 6×/wk, with weekly occupational therapist coaching visits. MEASURES: Weekly repeated measures were the Hand Assessment in Infants (HAI) and Goal Attainment Scaling (GAS). Feasibility and relevance were assessed with a logbook and a parental report, including 10 continuous 0-10 scaled questions. RESULTS: Six infants were included (2 with left and 4 with right brain lesions). Parents provided a mean 3.4 to 6.2 stimulation sessions/wk. Feasibility and relevance were highly rated (Ms = 8.2-9.6, SDs = 0.2-1.3). Stimulation significantly improved HAI bimanual and total scores for all infants, with no impact on HAI unilateral scores. GAS scores improved with stimulation (significant for 3 infants). CONCLUSIONS AND RELEVANCE: BB-Bim was feasible and tended to improve bimanual function in infants at risk of unilateral CP. What This Article Adds: Parent-provided daily bimanual stimulation at home is feasible when parents are coached weekly by an occupational therapist. Bimanual stimulation seems to improve functional interactions between the hands among infants at high risk of unilateral CP.

Hyperacute Recanalization Strategies and Childhood Stroke in the Evidence Age.

No controlled pharmacological studies are available in the field of pediatric stroke, except for sickle cell disease. Therefore, while pharmacological and mechanical recanalization treatments have repeatedly shown clinical benefit in adults with arterial ischemic stroke, pediatric strokologists still cannot base their therapeutic management (including hyperacute strategies) on high-level evidence. Once again, pediatricians face the same dichotomic choice: adapting adult procedures now versus waiting-for a long time-for the corresponding pediatric trials. One way out is building a compromise based on observational studies with large, longitudinal, comprehensive, real-life, and multisource dataset. Two recent high-quality observational studies have delivered promising conclusions on recanalization treatments in pediatric arterial ischemic stroke. TIPSTER (Thrombolysis in Pediatric Stroke Extended Results) showed that the risk of severe intracranial hemorrhage after intravenous thrombolysis is low; the Save Childs Study reported encouraging data about pediatric thrombectomy. Beyond the conclusion of a satisfactory global safety profile, a thorough analysis of the methods, populations, results, and therapeutic complications of these studies helps us to refine indications/contraindications and highlights the safeguards we need to rely on when discussing thrombolysis and thrombectomy in children. In conclusion, pediatric strokologists should not refrain from using clot lysis/retrieval tools in selected children with arterial ischemic stroke. But the implementation of hyperacute care is only feasible if the right candidate is identified through the sharing of common adult/pediatric protocols and ward collaboration, formalized well before the child's arrival. These anticipated protocols should never undervalue contraindications from adult guidelines and must involve the necessary pediatric expertise when facing specific causes of stroke, such as focal cerebral arteriopathy of childhood.

Reversible cerebral vasoconstriction syndrome in paediatric patients with systemic lupus erythematosus: implications for management.

Microvascular brain injury is well recognized in neuropsychiatric systemic lupus erythematosus (SLE), but cerebral large artery involvement is being debated. Three females with SLE, aged 9 to 14 years, had immunosuppressive treatment intensification because of lupus nephritis. Within the following days or weeks, they presented with intense cephalalgia - isolated or associated with neurological symptoms - and no or mild hypertension. Magnetic resonance angiography showed multiple stenoses within the circle of Willis. One patient had subsequent small subcortical cerebral infarction. Two patients were treated for neuropsychiatric SLE; one patient was treated for reversible cerebral vasoconstriction syndrome (RCVS). Angiography normalized within a few weeks in all three patients. Retrospectively, clinical and radiological features suggest that RCVS was the most likely diagnosis in all patients. Multidisciplinary analysis of clinical and angiographic features is recommended, as RCVS is rare in children and its recognition may help to adjust treatment. WHAT THIS PAPER ADDS: Reversible vasoconstriction syndrome was observed in paediatric systemic lupus erythematosus. Thorough imaging analysis was necessary to address this diagnosis in paediatric patients.

SÍNDROME DE VASOCONSTRICCIÓN CEREBRAL REVERSIBLE EN PACIENTES PEDIÁTRICOS CON LUPUS ERITEMATOSO SISTÉMICO: IMPLICANCIAS PARA EL MANEJO: La lesión microvascular cerebral está bien reconocida en el Lupus eritematoso sistémico neuropsiquiátrico (LES), pero se debate la participación de las arterias cerebrales grandes. Tres mujeres con LES, de edades entre 9 y 14 años, tuvieron una intensificación del tratamiento inmunosupresión por la nefritis lúpica. Dentro de los siguientes días o semanas, presentaron cefalea intensa, aislada o asociada con síntomas neurológicos - con o sin leve hipertensión. La angiografía por resonancia magnética mostro múltiples estenosis en el círculo de Willis. Un paciente tuvo subsecuentemente un pequeño infarto cerebral subcortical.

SÍNDROME DA VASOCONSTRIÇÃO CEREBRAL REVERSÍVEL EM PACIENTES PEDIÁTRICOS COM LUPUS ERITOMATOSO SISTÊMICO: IMPLICAÇÕES PARA O MANEJO: Lesão cerebral microvascular é bem reconhecida no lupus eritomatoso sistêmico (LES) neuropsiquiátrico, mas o envolvimento arterial cerebral extenso tem sido debatido. Três meninas com LES, idades de 9 a 14 anos, tiveram intensificação do tratamento imunossupressivo devido a nefrite causada pelo lupus. Dentro dos dias ou semanas seguintes, apresentaram cefalalgia intensa - isolada ou associada com sintomas neurológicos - sem nenhuma, ou com leve hipertensão. A angiografia por ressonância magnética mostrou estenoses múltiplas no círculo de Willis. Uma paciente teve subsequente infarto cerebral subcortical pequeno. Duas pacientes foram tratadas para LES neuropsiquiátrico, uma foi tratada para síndrome da vasoconstrição cerebral reversível (SVCR). A angiografia se normalizou em algumas semanas em todas as três pacientes. Retrospectivamente, os achados clínicos e radiológicos sugerem que SVCR era o diagnóstico mais provável em todas. Análise multidisciplinar dos aspectos clínicos e angiográficos é recomendada, pois a SVCR é rara em crianças, e seu reconhecimento pode ajudar a ajustar o tratamento.

Focal Cerebral Arteriopathy of Childhood: Novel Severity Score and Natural History.

Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.

When the vibrations allow for anticipating the force to be produced: an extend to Pfister et al. (2014).

According to the ideomotor theory, action selection is done by the mental anticipation of its perceptual consequences. If the distal information processed mainly by vision and hearing are considered essential for the representation of the action, the proximal information processed by the sense of touch and proprioception is of less importance. Recent works seem to show the opposite. Nevertheless, it is necessary to complete these results by offering a situation, more ecological, where response and effect can occur on the same effector. So, the goal of our work was to implement a more relevant spatial correspondence because to touch is not the same action that to hear or to see. To do so, participants pressed a specific key after the presentation of a stimulus. The key vibrated depending on the pressure exerted on it. In a compatible condition, high pressure on a key triggered a high vibration, while in an incompatible condition high pressure triggered a low vibration on the same effectors. As expected, the response times were faster in the compatible condition than the incompatible condition. This means that proximal information participates actively in the selection of action.

Manual dexterity, but not cerebral palsy, predicts cognitive functioning after neonatal stroke.

AIM: To disentangle the respective impacts of manual dexterity and cerebral palsy (CP) in cognitive functioning after neonatal arterial ischaemic stroke. METHOD: The population included 60 children (21 females, 39 males) with neonatal arterial ischaemic stroke but not epilepsy. The presence of CP was assessed clinically at the age of 7 years and 2 months (range 6y 11mo-7y 8mo) using the definition of the Surveillance of CP in Europe network. Standardized tests (Nine-Hole Peg Test and Box and Blocks Test) were used to quantify manual (finger and hand respectively) dexterity. General cognitive functioning was evaluated with the Wechsler Intelligence Scale for Children, Fourth Edition. Simple and multiple linear regression models were performed while controlling for socio-economic status, lesion side, and sex. RESULTS: Fifteen children were diagnosed with CP. In simple regression models, both manual dexterity and CP were associated with cognitive functioning (ß=0.41 [p=0.002] and ß=0.31 [p=0.019] respectively). However, in multiple regression models, manual dexterity was the only associated variable of cognitive functioning, whether or not a child had CP (ß=0.35; p=0.007). This result was reproduced in models with other covariables (ß=0.31; p=0.017). INTERPRETATION: As observed in typically developing children, manual dexterity is related to cognitive functioning in children having suffered a focal brain insult during the neonatal period. WHAT THIS PAPER ADDS: Manual dexterity predicts cognitive functioning after neonatal arterial ischaemic stroke. Correlations between manual dexterity and cognitive functioning occur irrespective of sex, lesion side, presence of cerebral palsy, and socio-economic status. Residual motor ability may support cognitive functioning.

Loss of α1ß1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia.

Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1ß1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.

Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke.

AIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function. METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test. RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p<0.001, without differences of the non-motor corpus callosum area). In addition, there was a significant positive association between the motor part of the corpus callosum and both contralesional (Pr(>|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated. INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies.

[Diagnosis and emergency treatment of stroke in children]. / Diagnostic et prise en charge en urgence de l'accident vasculaire cérébral de l'enfant.

The sudden occurrence of a focal neurological deficit, sometimes transitory and fluctuating, must lead to a suspicion of a stroke, including in a child. The preferred examination is magnetic resonance imaging with magnetic resonance angiography in an emergency. The sequelae of stroke are common and severe. Urgent diagnosis and adapted care can help to improve morbidity-mortality. Rehabilitation starts early and must systematically screen for cognitive or language impairment. The management of a stroke in a child must be planned for in multi-disciplinary protocols established before the patient's arrival at hospital.

[Life after a neonatal cerebral infarction, the experience of the AVCnn cohort]. / Vivre après un infarctus cérébral néonatal, expérience de la cohorte AVCnn.

The neonatal arterial cerebral infarction is a clinical model for the study of development after early brain damage. The data from the AVCnn cohort, a French multicentre study, show that severe sequelae are rare while the least severe involve numerous areas of activity and concern the majority of children. The cosegregation of different forms of deficiency is significant.

Does Contralesional Hand Function After Neonatal Stroke Only Depend on Lesion Characteristics?

BACKGROUND AND PURPOSE: In children having suffered from neonatal arterial ischemic stroke, the relationship between contralesional hand performance and structural changes in brain areas remote from the infarct site was examined. METHODS: Using voxel-based morphometry, we correlated contralesional gross manual dexterity assessed by the box and block test and whole-brain gray and white-matter volume changes on high-resolution magnetic resonance imaging in 37 7-year-old post-neonatal arterial ischemic stroke children. We also compared the volume of the identified structures with magnetic resonance imaging data of 10 typically developing age-matched children. RESULTS: Areas showing the highest positive correlation with the box and block test scores were ipsilesional mediodorsal thalamus, contralesional cerebellar lobule VIIa Crus I, and ipsilesional corticospinal tract at the level of superior corona radiata, the posterior limb of the internal capsule, and the cerebral peduncle and the ipsilesional body of corpus callosum. When compared with typically developing age-matched children, post-neonatal arterial ischemic stroke children with severe contralesional hand motor deficit exhibited significant volume reductions in these structures (except the cerebellum), whereas no differences were found with those with good manual dexterity. No negative correlation was found between box and block test scores and brain areas. CONCLUSIONS: Contralesional hand performance after neonatal arterial ischemic stroke is correlated with atrophy in brain areas directly or functionally connected but anatomically remote from the infarct. Our study suggests a role of the cerebellar lobule VIIa Crus I and mediodorsal thalamus in manual dexterity. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02511249.

Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke.

OBJECTIVES: To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes. STUDY DESIGN: A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation. Thus, 80 families completed the 7-year clinical assessment. Epileptic status, schooling, motor abilities, global intellectual functioning, spoken language, and parental opinions were recorded. Principal component analysis was applied. RESULTS: Rates of impaired language, cerebral palsy, low academic skills, active epilepsy, and global intellectual deficiency were 49%, 32%, 28%, 11%, and 8%, respectively. All were highly correlated. Eventually, 59% of children were affected by at least 1 of the aforementioned conditions. In 30% of cases, the viewpoints of health practitioners and parents did not match. CONCLUSION: The prevalence of severe disabilities at 7 years after NAIS is low, but most children exhibit some impairment in developmental profile. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02511249), Programme Hospitalier de Recherche Clinique Régional (0308052), Programme Hospitalier de Recherche Clinique Interrégional (1008026), and EudraCT (2010-A00329-30).

Long term motor function after neonatal stroke: Lesion localization above all.

Motor outcome is variable following neonatal arterial ischemic stroke (NAIS). We analyzed the relationship between lesion characteristics on brain MRI and motor function in children who had suffered from NAIS. Thirty eight full term born children with unilateral NAIS were investigated at the age of seven. 3D T1- and 3D FLAIR-weighted MR images were acquired on a 3T MRI scanner. Lesion characteristics were compared between patients with and without cerebral palsy (CP) using the following approaches: lesion localization either using a category-based analysis, lesion mapping as well as voxel-based lesion-symptom mapping (VLSM). Using diffusion-weighted imaging the microstructure of the cortico-spinal tract (CST) was related to the status of CP by measuring DTI parameters. Whereas children with lesions sparing the primary motor system did not develop CP, CP was always present when extensive lesions damaged at least two brain structures involving the motor system. The VLSM approach provided a statistical map that confirmed the cortical lesions in the primary motor system and revealed that CP was highly correlated with lesions in close proximity to the CST. In children with CP, diffusion parameters indicated microstructural changes in the CST at the level of internal capsule and the centrum semiovale. White matter damage of the CST in centrum semiovale was a highly reproducible marker of CP. This is the first description of the implication of this latter region in motor impairment after NAIS. In conclusion, CP in childhood was closely linked to the location of the infarct in the motor system.