Deep Brain Stimulation for GNAO1-Associated Dystonia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Guanine nucleotide-binding protein alpha-activating activity polypeptide O (GNAO1) syndrome, a rare congenital monogenetic disorder, is characterized by a neurodevelopmental syndrome and the presence of dystonia. Dystonia can be very pronounced and even lead to a life-threatening status dystonicus. In a small number of pharmaco-refractory cases, deep brain stimulation (DBS) has been attempted to reduce dystonia. In this study, we summarize the current literature on outcome, safety, and outcome predictors of DBS for GNAO1-associated dystonia. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis on individual patient data. We included 18 studies describing 28 unique patients. RESULTS: The mean age of onset of symptoms was 2.4 years (SD 3.8); 16 of 28 patients were male, and dystonia was nearly always generalized (20/22 patients). Symptoms were present before DBS for a median duration of 19.5 months, although highly variable, occurring between 3 and 168 months. The exact phenotype, genotype, and radiologic abnormalities varied and seemed to be of little importance in terms of DBS outcome. All studies described an improvement in dystonia. Our meta-analysis focused on pallidal DBS and found an absolute and relative improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) of 32.5 points (37.9%; motor part; p = 0.001) and 5.8 points (21.5%; disability part; p = 0.043) at last follow-up compared with preoperative state; 80% of patients were considered responders (BFMDRS-M reduction by ≥25%). Although worsening over time does occur, an improvement was still observed in patients after >10 years. All reported cases of status dystonicus resolved after DBS surgery. Skin erosion and infection were observed in 18% of patients. CONCLUSION: Pallidal DBS can be efficacious and safe in GNAO1-associated dystonia.

The Impact of Intraventricular Hemorrhage and Periventricular Leukomalacia on Mortality and Neurodevelopmental Outcome in Very Preterm and Very Low Birthweight Infants: A Prospective Population-based Cohort Study.

OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.

Autologous iPSC-Derived Human Neuromuscular Junction to Model the Pathophysiology of Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a heterogeneous group of genetic neurodegenerative disorders, characterized by progressive lower limb spasticity and weakness resulting from retrograde axonal degeneration of motor neurons (MNs). Here, we generated in vitro human neuromuscular junctions (NMJs) from five HSP patient-specific induced pluripotent stem cell (hiPSC) lines, by means of microfluidic strategy, to model disease-relevant neuropathologic processes. The strength of our NMJ model lies in the generation of lower MNs and myotubes from autologous hiPSC origin, maintaining the genetic background of the HSP patient donors in both cell types and in the cellular organization due to the microfluidic devices. Three patients characterized by a mutation in the SPG3a gene, encoding the ATLASTIN GTPase 1 protein, and two patients with a mutation in the SPG4 gene, encoding the SPASTIN protein, were included in this study. Differentiation of the HSP-derived lines gave rise to lower MNs that could recapitulate pathological hallmarks, such as axonal swellings with accumulation of Acetyl-α-TUBULIN and reduction of SPASTIN levels. Furthermore, NMJs from HSP-derived lines were lower in number and in contact point complexity, denoting an impaired NMJ profile, also confirmed by some alterations in genes encoding for proteins associated with microtubules and responsible for axonal transport. Considering the complexity of HSP, these patient-derived neuronal and skeletal muscle cell co-cultures offer unique tools to study the pathologic mechanisms and explore novel treatment options for rescuing axonal defects and diverse cellular processes, including membrane trafficking, intracellular motility and protein degradation in HSP.

Complication rate after scoliosis surgery in children with cerebral palsy.

Scoliosis is an important problem in children with cerebral palsy (CP). However, the choice for a spinal fusion has to be weighed against the risks of major surgery in this vulnerable population. Paediatricians are frequently consulted preoperatively to assess the (respiratory) risk involved, but data on this question specific for CP are rare. Therefore, we investigated the complication rate after scoliosis surgery in children with CP, compared to idiopathic scoliosis (IS), and we searched for risk factors for the most common complications. In a retrospective monocenter study we analyzed the medical records from all children with CP and IS undergoing scoliosis surgery from 2010 until 2014. Duration of hospitalization and postoperative complications were compared within a 6-month follow-up. Univariate and multivariate logistic regression models were used to identify risk factors. The study included 44 patients with CP (mean age 15y0mo) and 78 patients with IS (mean age 14y6mo). Children with CP experience a higher rate of complications : respiratory and cardiovascular, as well as wound infections and decubitus ulcers (p<0.05). Postoperative pneumonia was the most frequent complication in both patient groups (43% and 18% in CP and IS respectively), with epilepsy being a significant risk factor (OR 3.85, p= 0.037) in children with CP. Intensive care unit and total hospital stay were longer in the CP group (p<0.001). These results may add information on perioperative care and surgical decision making.

Critical Coarctation of the Aorta in Selective Fetal Growth Restriction and the Role of Coronary Stent Implantation.

INTRODUCTION: Monochorionic twins are at increased risk of congenital heart defects (CHDs). Up to 26% have a birth weight <1,500 g, a CHD requiring neonatal surgery, therefore, poses particular challenges. OBJECTIVE: The aim of the study was to describe pregnancy characteristics, perinatal management, and outcome of monochorionic twins diagnosed with critical coarctation of the aorta (CoA). METHODS: We included monochorionic twins diagnosed with critical CoA (2010-2019) at 2 tertiary referral centers, and we systematically reviewed the literature regarding CoA in monochorionic twins. RESULTS: Seven neonates were included. All were the smaller twin of pregnancies complicated by selective fetal growth restriction. The median gestational age at birth was 32 weeks (28-34). Birth weight of affected twins ranged as 670-1,800 g. One neonate underwent coarctectomy at the age of 1 month (2,330 g). Six underwent stent implantation, performed between day 8 and 40, followed by definitive coarctectomy between 4 and 9 months in 4. All 7 developed normally, except for 1 child with neurodevelopmental delay. Three co-twins had pulmonary stenosis, of whom 1 required balloon valvuloplasty. The literature review revealed 10 cases of CoA, all in the smaller twin. Six cases detected in the first weeks after birth were treated with prostaglandins alone, by repeated transcatheter angioplasty or by surgical repair, with good outcome in 2 out of 6. CONCLUSIONS: CoA specifically affects the smaller twin of growth discordant monochorionic twin pairs. Stent implantation is a feasible bridging therapy to surgery in these low birth weight neonates.

The relationship between neuroimaging and motor outcome in children with cerebral palsy: A systematic review - Part A. Structural imaging.

BACKGROUND: Conventional Structural Magnetic Resonance Imaging (sMRI) is a mainstay in Cerebral Palsy (CP) diagnosis. AIMS: A systematic literature review was performed with the aim to investigate the relationship between structural brain lesions identified by sMRI and motor outcomes in children with CP. METHODS: Fifty-eight studies were included. The results were analysed in terms of population characteristics, sMRI (classified according to Krägeloh-Mann & Horber, 2007), gross and fine motor function and their interrelation. OUTCOMES: White matter lesions were the most common brain lesion types and were present in 57.8 % of all children with uCP, in 67.0 % of all children with bCP and in 33 % of the group of mixed subtypes. Grey matter lesions were most frequently registered in children with dyskinesia (n = 42.2 %). No structural anomalies visualized by sMRI were reported in 5.7 % of all cases. In all lesion types, an equal distribution over the different gross motor function classification system categories was present. The included studies did not report sufficient information about fine motor function to relate these results to structural imaging. CONCLUSIONS AND IMPLICATIONS: The relationship between brain structure and motor outcome needs to be further elucidated in a representative cohort of children with CP, using a more standardized MRI classification system.

Long-term outcomes of very low birth weight infants with spontaneous intestinal perforation: A retrospective case-matched cohort study.

BACKGROUND: Spontaneous intestinal perforation (SIP) is an intestinal complication that occurs in very ill preterms. We investigated whether SIP survivors have worse neurodevelopmental and gastrointestinal outcomes and a poorer quality of life than controls. METHODS: A retrospective case-matched cohort study was performed involving infants treated for SIP in a NICU between August 1994 and April 2014. Controls and SIP patients were matched to gestational age, gender, and birth period. Medical records were reviewed. Telephone surveys were conducted to evaluate the medical condition, quality of life (PedsQL™ 4.0), neuropsychiatric and gastrointestinal outcome. McNemar's and Wilcoxon tests were performed, and generalized linear models were computed. RESULTS: Forty-nine SIP patients were included. The percentages of children with multiple disabilities (40% vs. 17%, OR = 3.3) and requiring physiotherapy (86% vs. 60%, OR = 4.77) were higher in the SIP group than in the control group. Intraventricular hemorrhage (IVH) led to a worse neurodevelopmental outcome regardless of SIP (OR = 8.79 for disability), and female gender was a protective factor against disability (OR = 0.06). Reported quality of life and gastrointestinal comorbidities did not differ between the two groups. CONCLUSION: SIP survivors tend to be at risk of multiple disabilities. IVH and female gender influence the neurodevelopmental outcome regardless of SIP. LEVELS OF EVIDENCE: Level III: case-control study.

Integrity of the inferior longitudinal fasciculus and impaired object recognition in children: a diffusion tensor imaging study.

AIM: In this study, we explored the integrity of the inferior longitudinal fasciculus (ILF) by means of diffusion tensor imaging tractography in children with visual perceptual impairment, and more specifically, object recognition deficits, compared with typically developing children. METHODS: Eleven individuals (nine males, two females; mean age 7 y 8 mo; range 3 y 5 mo-13 y) were assessed with the L94 visual perceptual battery after assessment of performance age. In all participants, an ophthalmological evaluation was carried out. Diffusion tensor imaging tractography of the ILF was performed. The mean fractional anisotropy was determined for every child and compared with data for 11 age- and sex-matched typically developing children. RESULTS: The mean fractional anisotropy value in the left ILF was consistently lower in the study participants than in the comparison group. The five children with L94 impairment showed a significantly lower ILF fractional anisotropy on the left as well as on the right side. Furthermore, the decrease in ILF fractional anisotropy was correlated with the number of impaired subtests. INTERPRETATION: The results suggest an association between ILF integrity loss and object recognition deficits. Moreover, the severity of clinical impairment is reflected in the degree of ILF integrity loss. Therefore, the ILF plays a potential role in object recognition.

Risk factors for neurodevelopment impairment in twin-twin transfusion syndrome treated with fetoscopic laser surgery.

OBJECTIVE: To estimate the risk factors for adverse long-term neurodevelopment outcome in twin-twin transfusion syndrome treated with laser surgery. METHODS: Twin-twin transfusion syndrome cases treated with laser surgery at three European centers from August 2000 to December 2005 were included in this case-control study. Neurological, mental, and psychomotor development (using the Bayley Scales of Infant Development, 2nd edition) was evaluated at 2 years of age. RESULTS: A total of 212 twin-twin transfusion syndrome pregnancies were treated with laser surgery during the study period. Overall mortality rate was 30% (129 of 424). Seventeen children (6%) were lost to follow-up. Long-term outcome was assessed in 278 infants. The incidence of neurodevelopment impairment was 18% (50 of 278). Four risk factors were found to be significantly associated with increased risk for neurodevelopment impairment: greater gestational age at laser surgery (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.00-1.69; P=.05), higher Quintero stage (OR 3.55 for each increment in stage, 95% CI 1.07-11.82, P=.04), lower gestational age at birth (OR 1.39 for each week, 95% CI 1.06-1.81; P=.01), and lower birth weight (OR 1.18 for each 100-g decrease, 95% CI 1.05-1.32; P<.01). In a multivariable analysis, lower gestational age at birth was the only factor independently associated with neurodevelopmental impairment (OR 1.33 for each week, 95% CI 1.05-1.67, P=.02). CONCLUSION: Neurodevelopment impairment in twin- twin transfusion syndrome survivors treated with laser surgery is associated with advanced gestational age at laser surgery, low gestational age at birth, low birth weight, and high Quintero stage. LEVEL OF EVIDENCE: II.

Motor function following multilevel botulinum toxin type A treatment in children with cerebral palsy.

This study evaluated the effects of multilevel botulinum toxin type A (BTX-A) treatments on the gait pattern of children with spastic cerebral palsy (Gross Motor Function Classification System Levels I-III). In this nested case-control design, 30 children (mean age 6y 11mo [SD 1y 5mo]; 21 males, nine females; 19 with hemiplegia, 11 with diplegia) were treated according to best practice guidelines in paediatric orthopaedics, including BTX-A injections. A matched control group of 30 children (mean age 7y 8mo [SD 1y 10mo]; 13 males, 17 females; 19 with hemiplegia, 11 with diplegia) were treated identically, but without BTX-A. Motor development status at 5 to 10 years of age was assessed by means of three-dimensional gait analysis at a mean time of 1 year 10 months (SD 10mo) after the last BTX-A treatment. The control group showed a significantly more pronounced pathological gait pattern than the BTX-A group. Major differences were found for pelvic anterior tilt, maximum hip and knee extension, and internal hip rotation. These results provide evidence for a prolonged effect of BTX-A and suggest that BTX-A injections, in combination with common conservative treatment options, result in a gait pattern that is less defined by secondary problems (e.g. bony deformities) at 5 to 10 years of age, minimizing the need for complex surgery at a later age and enhancing quality of life.