Stratification of neurogenic bladder risk in spina bifida using the urinary peptidome.

Neurogenic bladder poses a major morbidity in children with spina bifida (SB), and videourodynamic studies (VUDS) are used to stratify this risk. This small-scale pilot study utilized current mass-spectrometry-based proteomic approaches to identify peptides or proteins in urine that may differentiate children at high risk of developing renal complications from a neurogenic bladder. Twenty-two urine samples of which nine had high bladder pressure storage that put the upper urinary tract at risk, while 13 with a lower risk for renal compromise were analyzed. More than 1,900 peptides across all 22 samples were quantified, and 115 peptides differed significantly (P < 0.05) between the two groups. Using machine learning approaches five peptides that showed the greatest differences between these two clinical categories were used to build a classifier. We tested this classifier by blind analysis of an additional six urine samples and showed that it correctly assigned the unknown samples in their proper risk category. These promising results indicate that a urinary screening test based on peptides could be performed on a regular basis to stratify the neurogenic bladder into low or high-risk categories. Expanding this work to larger cohorts as well as across a broad spectrum of urodynamics outcomes may provide a useful diagnostic test for neurogenic bladder.NEW & NOTEWORTHY This approach could help risk stratify the neurogenic bladder in patients with spina bifida and could allow us to safely defer on up to 1/3 of urodynamic studies. These pilot data justify a larger trial before this approach becomes a clinical tool.

Prenatal imaging of the normal and abnormal spinal cord: recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee.

Spinal dysraphisms are amenable to diagnosis in utero. The prognosis and the neonatal management of these conditions differ significantly depending on their types, mainly on the distinction between open and closed defects. A detailed evaluation not only of the fetal spine, but also of the brain, skull, and lower limbs is essential in allowing for the right diagnosis. In this article, recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee will be presented. The aim of this paper is to review the imaging features of the normal and abnormal fetal spinal cord, to clarify the prenatal classification of congenital spinal cord anomalies and to provide guidance in their reporting.

Midline cutaneous anomalies of the craniospinal axis.

Patients with midline cutaneous anomalies of the craniospinal axis can be indicative of underlying embryonic defects, such as neural tube defects. Lack of familiarity with these midline aberrant skin findings may lead to misdiagnosis and delayed treatment. In this review, midline cutaneous anomalies of the craniospinal axis including aplasia cutis congenita, cranial and spinal dysraphism, and other developmental anomalies are explored in detail with emphasis on cutaneous clues to the diagnosis and appropriate workup.

Ischemic myelomalacia and closed spinal dysraphism in multiple finishing swine.

Ischemic myelomalacia secondary to fibrocartilaginous emboli (FCE) is an idiopathic disease in humans and animals. On the other hand, congenital spinal cord malformations result from neural tube defects in fetal development (ie, spinal dysraphism), with structural anomalies referred to collectively as myelodysplasia. Spinal dysraphisms are frequently accompanied by skin and vertebral abnormalities because of the embryogenic relationship. In this observational case study, we report the pathologic findings of 13, 18- to 24-weeks-old pigs from a large conventional operation that presented with acute paraparesis. Ischemic myelomalacia secondary to FCE was observed in 5 of 13 examined pigs. Congenital spinal cord malformations located between the caudal thoracic and sacral spinal cord were identified in 7 pigs, with structural abnormalities that ranged from diplomyelia/split cord malformation to segmental spinal dysgenesis (myelodysplasia) to caudal agenesis. Concurrent myelomalacia and congenital spinal cord malformations in the same or different sites were noted in 2 pigs. No spinal lesion was observed in 3 pigs. Although gross vertebral abnormalities were not observed herein, intervertebral instability due to minor defects in the articular facets, as well as other unidentified factors, is suspected to contribute high incidence of FCE. It is likely that these congenital malformations were previously underdiagnosed or are possibly new conditions associated with continuous inbreeding and genetic improvement in the modern swine industry.

Electrodiagnosis has a potential to identify neural damage in asymptomatic infants with closed spinal dysraphism.

PURPOSE: The presence and progression of symptoms is the basis for deciding to perform surgery in infants with closed spinal dysraphism (CSD); however, identifying symptoms could be limited, making it difficult to decide. This study investigated whether an electrodiagnostic study (EDS) can provide evidence of neural damage in asymptomatic infants with CSD. METHODS: The study group comprised infants with CSD suspected of having neural damage based on structural abnormalities in spinal ultrasound findings. The patients' medical records were reviewed retrospectively for their clinical presentation, neuroimaging findings, urodynamic study (UDS) results, EDS findings, and surgical status. RESULTS: Among 125 infants who underwent EDS and UDS, 117 (94%) had no clinical symptoms, except for cutaneous manifestations. Among these asymptomatic patients, 51 individuals (43.6%) had abnormal EDS findings; 33 subjects (28.2%) showed abnormal findings on EDS alone, while 37 (31.6%) on UDS alone, and 18 (15.4%) on both EDS and UDS. Chi-square test showed an opposite relationship between the two test results; when EDS was abnormal, UDS was often normal and vice versa (χ2 = 5.328, p = 0.021). In all cases with abnormal EDS, denervation potentials, such as fibrillation and positive sharp waves, were observed on needle electromyography. However, abnormal findings in the nerve conduction study were observed only in six cases. CONCLUSION: Subclinical neural damage was identified through EDS in asymptomatic infants with CSD. EDS could be necessary to determine whether follow-up monitoring only or surgical intervention is required for this patient group complementing UDS findings.

Electrodiagnostic findings of retethering in children with spinal dysraphism.

PURPOSE: Retethering of the cord can occur after the initial untethering surgery. Typical neurological manifestations indicative of cord tethering are often difficult to determine in pediatric patients. Patients who had a primary untethering operation are likely to present with some degree of neurological deficits from a previous tethering event, and urodynamic studies (UDSs) and spine images are frequently abnormal. Therefore, more objective tools to detect retethering are needed. This study sought to delineate the characteristics of EDS of retethering, and therefore, could support the diagnosis of retethering. METHODS: Among 692 subjects who had an untethering operation, data from 93 subjects who had been suspected of retethering clinically were retrospectively extracted. The subjects were divided into two groups, a retethered group, and a non-progression group, according to whether or not surgical interventions had been performed. Two consecutive EDSs, clinical findings, spine magnetic resonance imaging scans, and UDSs before the development of new tethering symptoms were reviewed and compared. RESULTS: In the electromyography (EMG) study, the appearance of abnormal spontaneous activity (ASA) in new muscles was prominent in the retethered group (p < 0.01). The loss of ASA was more pronounced in the non-progression group (p < 0.01). Specificity and sensitivity of EMG for retethering were 80.4 and 56.5%, respectively. In the nerve conduction study, the two groups did not show differences. The size of fibrillation potential was not different between the groups. CONCLUSIONS: To provide support for a clinician's decision on retethering, EDS could be an advantageous tool with high specificity when the results are compared to previous EDS results. Routine follow-up EDS post-operatively is recommended as a baseline for comparison at the time when retethering is clinically suspected.

Variation in Definitions of Kidney Abnormality in Patients with Spina Bifida: A Systematic Scoping Review.

PURPOSE: We systematically reviewed the variability in definitions of kidney abnormality (KA) outcomes in individuals with spina bifida (SB). MATERIALS AND METHODS: A systematic scoping review was conducted using MEDLINE, Embase™, Cochrane Library, CINAHL, PsycInfo®, Web of Science™ and ClinicalTrials.gov for articles from time of database inception to September 2020. No language or patient age restrictions were applied. Primary research articles involving individuals with SB where KA was assessed as an outcome were included. Means of assessing KA and defining KA severity were abstracted. RESULTS: Of 2,034 articles found, 274 were included in the review. Most articles were published after 1990 (63.5%) and included pediatric-only populations (0-18 years; 60.5%). KA outcomes were identified by imaging-based anatomical outcomes (84.7%), serum-based outcomes (44.9%), imaging-based functional outcomes (5.5%), urine-based outcomes (3.3%) and diagnoses of end-stage kidney disease (2.6%) or chronic kidney disease otherwise unspecified (1.8%). Hydronephrosis was the most commonly used specific outcome (64.6%, 177/274) with 19.8% (35/177) of articles defining hydronephrosis severity. Hydronephrosis was used more frequently in articles with pediatric-only populations. Creatinine and cystatin-C were used in 82.1% (101/123) and 17.9% (22/123) of articles reporting serum-based outcomes, respectively, with 32.7% and 50.0% of articles defining estimated glomerular filtration rate (GFR) severity. Serum-based outcomes were more common in articles including adults >18 years. Measured GFR was assessed in 9.9% (27/274) of articles, with 44.4% (12/27) of articles defining GFR severity. CONCLUSIONS: Significant variability exists in how authors define KA with few specifically defining KA severity. Consensus and consistency in defining KA outcomes are needed.

Cerebral Abnormalities in Spina Bifida: A Neuropathological Study.

INTRODUCTION: Spina bifida (SB) is the most common neural tube defect in humans. Here, we analyzed systematically the neuropathological findings of the brain in SB cases. METHODS: 79 cases with SB aperta (SBA) and 6 cases with SB occulta (SBO) autopsied at the Charité Neuropathology from 1974 to 2000 were re-evaluated retrospectively. For this, case files and spinal cord as well as brain sections were studied. RESULTS: While no brain malformations were detected in SBO cases, 95% of SBA cases had brain malformations. Main brain anomalies identified were hydrocephalus (71%), Chiari II malformation (36%), heterotopia (34%), other cerebellar anomalies (36%), gyrification defects (33%), and ependymal denudation (29%). Hydrocephalus was observed as early as gestational week 17 and was highly associated to Chiari II and ependymal denudation. In 55% SBA was accompanied by further anomalies not primarily affecting the CNS. CONCLUSION: We confirm using neuropathologic methods brain malformations in most SBA but none in SBO cases. In addition to our previous radiologic study, we now demonstrate the high prevalence of cerebellar malformations and cerebral heterotopias in SBA. The early detection of hydrocephalus and Chiari II malformation in fetuses raises the question whether these arise parallel rather than in strict temporal sequence.

A case report of serpentine-like syndrome and review of literature.

BACKGROUND: Serpentine-like syndrome (SLS) is a rare foetal abnormality, characterized by brachioesophagus, secondary intrathoracic stomach and vertebral deformity. Herein, we report a case of SLS diagnosed based on imaging, genetic examination and autopsy findings. CASE PRESENTATION: From the 19th to 23rd weeks of gestation, the foetus presented with brachioesophagus, secondary intrathoracic stomach, intrathoracic spleen with poly-spleen malformation, spinal deformity and diaphragm dysplasia, and some abdominal organs were partly located in the thoracic cavity. After extensive counselling, the couple opted to terminate the pregnancy. Whole genome sequencing and autopsy were performed. Then, the foetus was diagnosed with SLS. DISCUSSION AND CONCLUSIONS: SLS is characterized by multiorgan deformities and is associated with poor prognosis. Multiorgan deformities can be detected on prenatal sonography using three-dimensional ultrasound technology.

Investigating the landscape and trajectory of spina bifida research in Asia: a bibliometric analysis.

BACKGROUND: Spina bifida is a type of a neural tube defect which affects 243.14 per 100,000 babies in Asia. Research articles on spina bifida have increased in the recent years. However, no study has focused on the research trends in this field in Asia. METHODS: A systematic review of literature on spina bifida in Asia was performed using the Scopus database from inception to 2020. All published studies on spina bifida conducted in or published by authors from Asia were included in our analysis. Bibliometric information was obtained from Scopus and bibliometrics diagrams were created using VOSviewer software. RESULTS: A total of 652 articles were obtained in this study. The number of publications showed an upward trend starting 2000s. The country with the greatest number of publications was Japan while All India Institute of Medical Sciences was the most productive institution in spina bifida research in Asia. The current focus of this field in Asia was prevalence of spina bifida, prenatal diagnosis, folic acid supplementation, and complications of spina bifida. Future areas of research in spina bifida include the genetic basis of neural tube defects and the use of stem cell technology as therapies for spina bifida. CONCLUSION: This is the first bibliometric analysis on spina bifida in Asia. It showed the trend and future areas of research on spina bifida in Asia. Despite the increase in scientific literature on spina bifida research, more research outputs and collaborations are needed especially in developing countries in Asia.

Split cord malformation concomitant with spinal teratoma without open spinal dysraphism.

PURPOSE: Split cord malformation (SCM) presenting concomitant with spinal teratoma without any open spinal dysraphism has rarely been reported in the literature. We aimed to make a systematic review and qualitative analysis of the literature about the topic and present the first case of SCM concomitant with spinal teratoma harboring papillary thyroid carcinoma (PTC) component. METHODS: Two big search tools (Pubmed/MEDLINE) and Scopus were used. The search strategy was compatible to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). An exemplary case of ours was also presented. RESULTS: There were 30 patients (15 pediatric and 15 adult). Female and male distribution was even. Median age of the patients was 18 years (range = 0-66 years). The most common presenting symptoms were back pain and lower limb weakness. Spinal teratoma and SCM mostly presented at thoracic/thoracolumbar region in children and lumbar region in adults. Surgical outcome was better in the children compared to the adults. CONCLUSION: Thoracolumbar region is the most common location for such entity in children, whereas lumbar region for the adults. Surgical resection should be done as much as possible under neuromonitorization. The resected material should be evaluated thoroughly not to miss any malign pathology. Surgical outcome is better when it is done at an early age.

Pediatric Spinal Cord Diseases.

Spinal cord diseases in pediatric patients are highly variable in terms of presentation, pathology, and prognosis. Not only do they differ with respect to each other but so too with their adult equivalents. Some of the most common diseases are autoimmune (ie, multiple sclerosis, acute disseminated encephalomyelitis, and acute transverse myelitis), congenital (ie, dysraphism with spina bifida, split cord malformation, and tethered cord syndrome), tumor (ie, juvenile pilocytic astrocytoma, ependymoma, and hem-angioblastoma), and vascular (ie, cavernous malformations, arteriovenous malformations, and dural arteriovenous fistulas) in nature. These each require their own niche treatment paradigm and prognosis. Furthermore, presentation of different spinal cord diseases in children can be difficult to discern without epidemiologic and imaging data. Interpretation of these data is crucial to facilitating a timely and accurate diagnosis. Correspondingly, the aim of this review was to highlight the most pertinent features of the most common spinal cord diseases in the pediatric population.

Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

Concomitant Heterotopic Pancreas and Endometriosis as a Rare Cause of Ileo-Ileal Intussusception in a Young Woman with Spina Bifida: Case Report and Literature Review.

INTRODUCTION: Isolated heterotopic pancreas (HP) as the primary cause of bowel intussusception is extremely rare. We report a case of a 33-year-old female patient with spina bifida admitted to the Emergency Surgical Department for ileal intussusception due to the presence of heterotopic pancreas associated with endometriosis. AREAS COVERED: Symptomatic ileal intussusception for ectopic pancreas is usually associated with overt gastrointestinal blood loss (predominantly melena), abdominal pain, vomiting, and weight loss. Treatment is universally surgical. EXPERT COMMENTARY: Isolated heterotopic pancreas is a rare condition; it should be considered in the differential diagnosis of bowel intussusception.

Spinal dysraphism as a new entity in V.A.C.TE.R.L syndrome, resulting in a novel acronym V.A.C.TE.R.L.S.

Anorectal malformation (ARM) is the most common symptom in VACTERL syndrome (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies). The association of ARM and spinal dysraphisms (DYS) is well documented. We aim to better evaluate children with VACTERL association and ARM, considering the presence or not of DYS. Between 2000 and 2015, 279 children with VACTERL associations were identified in Necker Children's Hospital, Paris. We identified 61 VACTERL children (22%) with ARM. A total of 52 VACTERL children with ARM were included. DYS were identified in 36/52 of cases (69.2%). A total of 33 (63.5%) VACTERL children presented with sphincterial dysfunction. We constated that 28/33 (84.8%) of them had DYS + (p < 0.0001). More children in ARM (DYS +) subgroup are presenting with initial urinary sphincter dysfunction (58 vs 19%, p < 0.009) than ARM (DYS -). We identified 29 lipoma filum in our series, which were not statistically associated with urinary disorders (p = 0.143).Conclusion: We propose to refine the definition of VACTERL association, by adding S as Spinal defect to include it as an integral part of this syndrome, resulting in a novel acronym V.A.C.TE.R.L.S.What is Known:• The VACTERL association: congenital anomalies of the bony vertebral column (V), anorectal malformation (A), congenital cardiopathy (C), tracheo-esophageal defects (TE), renal and urinary tract anomalies (R), and limb malformations (L).• VACTERL children needs a complete appraisal, as early as possible, to adopt the most appropriate therapeutic management.What is New:• Include spine dysraphism (DYS) as a part of this syndrome, resulting in a novel acronym V.A.C.TE.R.L.S.• The significant correlation between VACTERL/DYS and urinary dysfunction requires to investigate the spine cord prenatally.

A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability.

Shprintzen-Goldberg syndrome (SGS) is a rare systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations. It is associated with a significant risk of intellectual disability, a feature which distinguishes it from Marfan and Loeys-Dietz syndromes. SGS is mainly caused by mutations in the SKI gene, a repressor of TGF-ß activity. Most SKI mutations are found in exon 1 of the gene and are located in the R-SMAD domain, a proposed hotspot for de novo mutations. Here, we report on a de novo SKI mutation located in the DHD domain of SKI. By adding our finding to previously reported de novo SKI mutations, a new mutational hotspot in the DHD domain is proposed. Our patient presented with a lipomeningomyelocele, tethered cord, and spina bifida but with no SGS-related clinical findings apart from a marfanoid habitus and long slender fingers. Specifically, she did not have an intellectual disability, craniofacial, or cardiovascular abnormalities. By comparing the clinical findings on patients with mutations in the R-SMAD and DHD domains of SKI, we propose that mutations in those domains have different effects on TGF-ß activity during embryonic development with resulting phenotypic differences.

Management of prenatally diagnosed spina bifida: how do we move ahead?

Linked Comment: Ultrasound Obstet Gynecol 2018; 53: 293-301 Linked Comment: Ultrasound Obstet Gynecol 2018; 53: 302-308 Linked Comment: Ultrasound Obstet Gynecol 2018; 53: 309-313.

Spina bifida screening in the first trimester using ultrasound biparietal diameter measurement adjusted for crown-rump length or abdominal circumference.

OBJECTIVE: Compare the performance of first trimester ultrasound biparietal diameter (BPD) screening for open spina bifida (OSB) when BPD is adjusted for crown-rump length (CRL) or abdominal circumference (AC). METHODS: For 63 OSB and 24 265 unaffected pregnancies, BPD was expressed as multiple of the normal median (MoM) based on CRL and on AC, and as the ratio BPD/AC. Screening performance was assessed by the Mahalanobis distance, the observed detection rate with normal fifth and 10th percentile cut-offs and the area under the receiver-operator characteristic curve (AUC). RESULTS: Mahalanobis distance for BPD MoM was considerably higher when based on AC than on CRL: 1.69 versus 1.14. Screening performance was also higher: using a fifth percentile cut-off, the detection rate was 59% compared with 41%; using a 10th percentile cut-off, the rates were 63% and 51%. Whilst the false-positives rates were slightly higher too-5.3% versus 5.1% and 10.8% versus 9.9%-the AUC was statistically significantly higher: 0.872 (95% CI, 0.816-0.928) compared with 0.735 (95% CI, 0.664-0.806). BPD/AC had intermediate performance. CONCLUSION: The best results are obtained when AC, rather than CRL, is used to express BPD values in MoMs. First trimester OSB screening can detect half to two-thirds of cases.

Quality of Life in Adolescents and Young Adults with and Without Spina Bifida: An Exploratory Analysis.

PURPOSE: The measurement of Quality of life (QOL) in adolescents and especially in adolescents with disabilities is limited, often by an assessment of function rather than perception. This analysis explores QOL in adolescents and young adults (AYA) with and without Spina Bifida (SB) from the perspective of AYA and their parents. DESIGN AND METHODS: A descriptive study using content analysis was conducted as a component of a larger multi-site mixed-method study of secondary conditions and adaptation. Participants responded to a single open-ended question on the meaning of quality of life. RESULTS: Descriptive accounts from 209 families generated the following shared categories: an engaged family, a positive life, the goal of independence, being healthy, essential needs for living, having friends, relying on faith, and romantic relationships. A unique category emerged from parents, doing what AYA wants to do. CONCLUSIONS: Family was the most frequently nominated component of QOL. The centrality of family in QOL is an important finding generally not assessed in measures of QOL or even less in health-related QOL instruments. PRACTICE IMPLICATIONS: Findings illustrate the importance of evaluating overall QOL from the perspective of AYA and their parents.

Intradetrusor Injections of Botulinum Toxin A in Adults with Spinal Dysraphism.

PURPOSE: The aim of the current study was to determine the outcomes of botulinum toxin A intradetrusor injections in adult patients with spina bifida. MATERIALS AND METHODS: All patients with spinal dysraphism who underwent intradetrusor injections of botulinum toxin A from 2002 to 2016 at a total of 14 centers were retrospectively included in analysis. The primary end point was the global success of injections, defined subjectively as the combination of urgency, urinary incontinence and detrusor overactivity/low bladder compliance resolution. Univariate and multivariate analysis was performed to seek predictors of global success. RESULTS: A total of 125 patients were included in study. The global success rate of the first injection was 62.3% with resolution of urinary incontinence in 73.5% of patients. All urodynamic parameters had improved significantly by 6 to 8 weeks compared to baseline, including maximum detrusor pressure (-12 cm H2O, p <0.001), maximum cystometric capacity (86.6 ml, p <0.001) and compliance (8.9 ml/cm H2O, p = 0.002). A total of 20 complications (3.6%) were recorded for the 561 intradetrusor botulinum toxin A injections, including 3 muscular weakness complications. The global success rate of the first injection was significantly lower in patients with poor compliance (34.4% vs 86.9%, OR 0.08, p <0.001). On multivariate analysis poor compliance was associated with a lower global success rate (OR 0.13, p <0.001). Female gender (OR 3.53, p = 0.01) and patient age (OR 39.9, p <0.001) were predictors of global success. CONCLUSIONS: Intradetrusor botulinum toxin A injections were effective in adult patients with spina bifida who had detrusor overactivity. In contrast, effectiveness was much lower in adult patients with spina bifida who had poor bladder compliance. The other predictors of global success were female gender and older age.