Diagnosis and Management of Tethered Cord Syndrome.

Tethered cord syndrome is a condition in which the spinal cord is tethered by pathological structures such as a tight filum terminale, intradural lipomas with or without a connecting extradural component, intradural fibrous adhesions, diastematomyelia, and neural placode adhesions following closure of a myelomeningocele.It usually occurs in childhood and adolescence as the spine grows in length, but it can also develop in adulthood. Symptoms of tethered cord syndrome are slowly progressive and varied. Incorrect diagnosis and inappropriate treatment may be provided if the physician lacks knowledge and understanding of this disease.This chapter aims to describe the pathophysiology, syndromes, diagnostic imaging, surgical treatment, and prognosis of tethered cord syndrome to enhance the understanding of this condition.

Understanding perspectives on neural tube defect management: insights from Jordanian parents.

INTRODUCTION: Neural tube defects (NTDs) represent a spectrum of heterogeneous birth anomalies characterized by the incomplete closure of the neural tube. In Jordan, NTDs are estimated to occur in approximately one out of every 1000 live births. Timely identification of NTDs during the 18-22 weeks of gestation period offers parents various management options, including intrauterine NTD repair and termination of pregnancy (TOP). This study aims to assess and compare parental knowledge and perceptions of these management modalities between parents of affected children and those with healthy offspring. MATERIALS AND METHODS: This retrospective case-control study was conducted at Jordan University Hospital (JUH) using telephone-administered questionnaires. Categorical variables were summarized using counts and percentages, while continuous variables were analyzed using mean and standard deviation. The association between exposure variables and outcomes was explored using binary logistic regression. Data analysis was performed using SPSS for Windows version 26 (SPSS Inc., Chicago, IL). RESULTS: The study sample comprised 143 participants, with 49.7% being parents of children with NTDs. The majority of NTD cases were associated with unplanned pregnancies, lack of folic acid supplementation, and postnatal diagnosis. Concerning parental knowledge of TOP in Jordan, 86% believed it to be legally permissible in certain situations. However, there was no statistically significant difference between cases and controls regarding attitudes toward TOP. While the majority of parents with NTD-affected children (88.7%) expressed a willingness to consider intrauterine surgery, this percentage decreased significantly (to 77.6%) after receiving detailed information about the procedure's risks and benefits (p = .013). CONCLUSIONS: This study represents the first case-control investigational study in Jordan focusing on parental perspectives regarding TOP versus intrauterine repair of myelomeningocele following a diagnosis of an NTD-affected fetus. Based on our findings, we urge the implementation of a national and international surveillance program for NTDs, assessing the disease burden, facilitating resource allocation toward prevention strategies, and promoting early diagnosis initiatives either by using newly suggested diagnostic biomarkers or early Antenatal ultrasonography.

Factors Affecting the Intensive Care Stay of Patients with Spinal Neural Tube Defects.

AIM: To evaluate the duration of hospitalization and the factors that increase this duration in cases treated in the neonatal intensive care unit with the diagnosis of a spinal neural tube defect (NTD). MATERIAL AND METHODS: The demographic characteristics, NTD type and level, ventriculoperitoneal (V-P) shunt needs, accompanying spinal deformity, antibiotherapy applied during treatment, and intensive care stay periods of 73 patients treated in our clinic between July 2017 and 2020 were retrospectively evaluated. RESULTS: The intensive care stay of NTD cases was 7?109 (mean=23) days. Fifty-one cases (69.9%) had myeloschisis, and 22 cases (30.1%) had myelomeningocele (MMC) sac. A V-P shunt was applied to 24 cases (32.9%) during hospitalization, and additional antibiotherapy was given to 32 (43.8%) cases. CONCLUSION: In myeloschisis cases compared with MMC marsupial cases, incidences of ventricular dilatation, kyphotic/scoliotic spine pathology, V-P shunt requirement, and longer hospital stay were observed. No difference in the duration of hospitalization was found in patients who underwent defect repair between the first day and 48 h after birth. However, the length of stay in hospital increased in patients operated on after 48 h. The period was longer in cases operated after seven days postnatally. Therefore, by performing NTD surgical treatment within the first 48 hours, the need for additional antibiotherapy and hospital stay can be shortened.

Transamniotic mesenchymal stem cell therapy for neural tube defects preserves neural function through lesion-specific engraftment and regeneration.

Neural tube defects (NTDs) lead to prenatal mortality and lifelong morbidity. Currently, surgical closure of NTD lesions results in limited functional recovery. We previously suggested that nerve regeneration was critical for NTD therapy. Here, we report that transamniotic bone marrow-derived mesenchymal stem cell (BMSC) therapy for NTDs during early development may achieve beneficial functional recovery. In our ex vivo rat embryonic NTD model, BMSCs injected into the amniotic cavity spontaneously migrated into the defective neural tissue. Hepatocyte growth factor and its receptor c-MET were found to play critical roles in this NTD lesion-specific migration. Using the in vivo rat fetal NTD model, we further discovered that the engrafted BMSCs specifically differentiated into the cell types of the defective tissue, including skin and different types of neurons in situ. BMSC treatment triggered skin repair in fetuses, leading to a 29.9 ± 5.6% reduction in the skin lesion area. The electrophysiological functional recovery assay revealed a decreased latency and increased motor-evoked potential amplitude in the BMSC-treated fetuses. Based on these positive outcomes, ease of operation, and reduced trauma to the mother and fetus, we propose that transamniotic BMSC administration could be a new effective therapy for NTDs.

miR-322 treatment rescues cell apoptosis and neural tube defect formation through silencing NADPH oxidase 4.

AIMS: Failure of neural tube closure resulting from excessive apoptosis leads to neural tube defects (NTDs). NADPH oxidase 4 (NOX4) is a critical mediator of cell growth and death, yet its role in NTDs has never been characterized. NOX4 is a potential target of miR-322, and we have previously demonstrated that miR-322 was involved in high glucose-induced NTDs. In this study, we investigated the effect of NOX4 on the embryonic neuroepithelium in NTDs and reveal a new regulatory mechanism for miR-322 that disrupts neurulation by ameliorating cell apoptosis. METHODS: All-trans-retinoic acid (ATRA)-induced mouse model was utilized to study NTDs. RNA pull-down and dual-luciferase reporter assays were used to confirm the interaction between NOX4 and miR-322. In mouse neural stem cells and whole-embryo culture, Western blot and TUNEL were carried out to investigate the effects of miR-322 and NOX4 on neuroepithelium apoptosis in NTD formation. RESULTS: NOX4, as a novel target of miR-322, was upregulated in ATRA-induced mouse model of NTDs. In mouse neural stem cells, the expression of NOX4 was inhibited by miR-322; still further, NOX4-triggered apoptosis was also suppressed by miR-322. Moreover, in whole-embryo culture, injection of the miR-322 mimic into the amniotic cavity attenuated cell apoptosis in NTD formation by silencing NOX4. CONCLUSION: miR-322/NOX4 plays a crucial role in apoptosis-induced NTD formation, which may provide a new understanding of the mechanism of embryonic NTDs and a basis for potential therapeutic target against NTDs.

Neurosurgical training and global health education: systematic review of challenges and benefits of in-country programs in the care of neural tube defects.

OBJECTIVE: The recognition that neurosurgeons harbor great potential to advocate for the care of individuals with neural tube defects (NTDs) globally has sounded as a clear call to action; however, neurosurgical care and training in low- and middle-income countries (LMICs) present unique challenges that must be considered. The objective of this study was to systematically review publications that describe the challenges and benefits of participating in neurosurgery-related training programs in LMICs in the service of individuals with NTDs. METHODS: Using MEDLINE (PubMed), the authors conducted a systematic review of English- and Spanish-language articles published from 1974 to 2019 that describe the experiences of in-country neurosurgery-related training programs in LMICs. The inclusion criteria were as follows-1) population/exposure: US residents, US neurosurgeons, and local in-country medical staff participating in neurosurgical training programs aimed at improving healthcare for individuals with NTDs; 2) comparison: qualitative studies; and 3) outcome: description of the challenges and benefits of neurosurgical training programs. Articles meeting these criteria were assessed within a global health education conceptual framework. RESULTS: Nine articles met the inclusion criteria, with the majority of the in-country neurosurgical training programs being seen in subregions of Africa (8/9 [89%]) and one in South/Central America. US-based residents and neurosurgeons who participated in global health neurosurgical training had increased exposure to rare diseases not common in the US, were given the opportunity to work with a collaborative team to educate local healthcare professionals, and had increased exposure to neurosurgical procedures involved in treating NTDs. US neurosurgeons agreed that participating in international training improved their own clinical practices but also recognized that identifying international partners, travel expenses, and interference with their current practice are major barriers to participating in global health education. In contrast, the local medical personnel learned surgical techniques from visiting neurosurgeons, had increased exposure to intraoperative decision-making, and were given guidance to improve postoperative care. The most significant challenges identified were difficulties in local long-term retention of trained fellows and staff, deficient infrastructure, and lower compensation offered for pediatric neurosurgery in comparison to adult care. CONCLUSIONS: The challenges and benefits of international neurosurgical training programs need to be considered to effectively promote the development of neurosurgical care for individuals with NTDs in LMICs. In this global health paradigm, future work needs to investigate further the in-country professionals' perspective, as well as the related outcomes.

Concepts in the neurosurgical care of patients with spinal neural tube defects: An embryologic approach.

BACKGROUND: The neural tube defects (NTDs) are a heterogeneous group of structural birth defects that arise from a complex array of multiple genetic and environmental factors and adversely affect the structure and function of the brain and spinal cord. Spinal NTDs are clinically more common than cranial NTDs. There remains a significant gap in linking the multiple NTD phenotypes to current genomic understanding. METHODS: This article summarizes the neurosurgical clinical approach to spinal NTDs by correlating each step of embryonic development of the human nervous system with key management concepts for defects that arise at that step. RESULTS: The NTDs are broadly classified as open or closed. Open defects include myelomeningocele (MMC), encephalocele, and anencephaly. Closed defects are also known as occult spinal dysraphism and are characterized by intact skin over the spinal defect. They are more common and often cause neurologic decline from tethered cord syndrome. Failure of primary neurulation gives rise to open myelomeningocele (MMC). Surgical closure of an open MMC focuses on realigning the tissue layers that failed to separate during neurulation. In utero closure is a promising recent technique. Chronic neurosurgical management largely focuses treating hydrocephalus. The Chiari II malformation is uniformly present in MMC patients and may cause brainstem dysfunction. Tethered spinal cord may progressively impair normal neurologic function but typically responds well to surgical untethering. CONCLUSIONS: Surgical closure of MMC centers on approximated realignment of embryologically disordered neural tissue. Clinical surgical management decisions in the spinal NTDs remains challenging but standardized principles have emerged.

Clubfoot and Tethered Cord Syndrome: Results of Treatment With the Ponseti Method.

BACKGROUND: The Ponseti technique has demonstrated high success rates worldwide for the treatment of idiopathic clubfoot. The purpose of this study was to determine whether clubfoot associated with tethered cord syndrome (TCS) was more resistant to Ponseti treatment than isolated clubfoot. METHODS: An IRB-approved retrospective cohort study of subjects undergoing Ponseti treatment of clubfoot between 2002 and 2013 was conducted. Subjects with TCS were matched to subjects with isolated clubfoot (1:2) on the basis of laterality, date of birth, sex, and age at presentation. Subject demographics, number of casts placed (pretenotomy and posttenotomy), and recurrence data were collected. Generalized logistic regression and linear mixed model regression analyses were used to compare recurrence within 2 years of the initiation of casting and the log number of casts needed to achieve an acceptable correction, respectively. RESULTS: Data from 24 subjects (16 isolated clubfeet, 8 with TCS) with clubfoot (12 bilateral, 12 unilateral) were analyzed. The isolated clubfoot group was the same age at presentation on average (21.9±4.7 d) as the TCS group (28.3±9.6 d) (P=0.55). The number of casts required to achieve an acceptable correction was 54% higher (95% CI, 7.8%-120.3%; P=0.0217) in the TCS group compared with the isolated clubfoot group. The cumulative crude incidence of deformity recurrence within the first 2 years after casting initiation was 8% in the isolated clubfoot group compared with 42% in the TCS group. The odds of deformity recurrence in the TCS group were 5.6 (95% CI, 0.7-45.2; P=0.1054) times the odds of deformity recurrence in the isolated clubfoot group. Furthermore, the incidence of deformity recurrence was higher among subjects who had a tethered cord release posttenotomy (56%, 5/9) as compared with pretenotomy (0%, 0/3). CONCLUSION: Clubfoot associated with TCS required more casts to achieve an acceptable correction. Subjects with tethered cord were also at an increased risk of deformity recurrence compared with subjects with isolated clubfoot. LEVEL OF EVIDENCE: Level II-retrospective prognostic study.

Transradial approach in the treatment of a sacral dural arteriovenous fistula: a technical note.

Sacral dural arteriovenous fistulas (SDAVFs) are rare, constituting no more than 10% of all spinal dural fistulas. They are most commonly fed by the lateral sacral artery (LSA), a branch of the internal iliac artery (IIA). Catheterization of this vessel requires either a crossover at the aortic bifurcation in cases of right femoral access or retrograde catheterization from the ipsilateral common femoral artery. We present the case of a 79-year-old man with tethered cord syndrome and a symptomatic SDAVF fed by two feeders from the left LSA. Spinal diagnostic angiography was made exceptionally challenging by an aorto-bi-iliac endograft, and selective catheterization of the left IIA was not possible. The patient could not undergo surgery due to multiple comorbidities, therefore embolization was considered the best approach. The procedure was carried out through a transradial access (TRA) with Onyx and n-butyl cyanoacrylate. The SDAVF was successfully treated and the patient made a full neurological recovery.

Excision and short segment fusion of a double ipsilateral lumbar hemivertebrae associated with a diastematomyelia and fixed pelvic obliquity.

We report the surgical treatment course of a 4-year-old girl with congenital scoliosis, diastematomyelia and double adjacent hemivertebrae. She had a lumbar curve with an apparent pelvic obliquity. Simultaneous excision of double segmented sequential hemivertebra at the L3-L4 level and fusion with short-segment instrumentation was performed via a posterior approach. Intraoperative radiographs revealed satisfactory curve correction and 0° pelvic obliquity. Following the excision of double adjacent hemivertebrae, three adjacent nerve roots were placed in one intervertebral foramen bilaterally. Nevertheless, no neurological deficit was developed, and the patient was able to ambulate with a brace at day one. Pelvic balance and deformity correction were maintained with no implant failure at the fifth year follow-up. Excision of two ipsilateral adjacent hemivertebra and short-segment posterior fusion performed via posterior-only approach simultaneously is an effective, safe, and less invasive technique for the treatment of the described case.

Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes.

We have established early-gestation chorionic villus-derived placenta mesenchymal stromal cells (PMSCs) as a potential treatment for spina bifida (SB), a neural tube defect. Our preclinical studies demonstrated that PMSCs have the potential to cure hind limb paralysis in the fetal lamb model of SB via a paracrine mechanism. PMSCs exhibit neuroprotective function by increasing cell number and neurites, as shown by indirect coculture and direct addition of PMSC-conditioned medium to the staurosporine-induced apoptotic human neuroblastoma cell line, SH-SY5Y. PMSC-conditioned medium suppressed caspase activity in apoptotic SH-SY5Y cells, suggesting that PMSC secretome contributes to neuronal survival after injury. As a part of PMSC secretome, PMSC exosomes were isolated and extensively characterized; their addition to apoptotic SH-SY5Y cells mediated an increase in neurites, suggesting that they exhibit neuroprotective function. Proteomic and RNA sequencing analysis revealed that PMSC exosomes contain several proteins and RNAs involved in neuronal survival and development. Galectin 1 was highly expressed on the surface of PMSCs and PMSC exosomes. Preincubation of exosomes with anti-galectin 1 antibody decreased their neuroprotective effect, suggesting that PMSC exosomes likely impart their effect via binding of galectin 1 to cells. Future studies will include in-depth analyses of the role of PMSC exosomes on neuroprotection and their clinical applications.-Kumar, P., Becker, J. C., Gao, K., Carney, R. P., Lankford, L., Keller, B. A., Herout, K., Lam, K. S., Farmer, D. L., Wang, A. Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes.

Neurological outcomes by mode of delivery for fetuses with open neural tube defects: a systematic review and meta-analysis.

BACKGROUND: Controversy exists regarding the optimal mode of delivery for fetuses with open neural tube defects. OBJECTIVE: To compare neurological outcomes among infants with open neural tube defects who underwent vaginal compared with caesarean delivery. SEARCH STRATEGY: Electronic databases MEDLINE, EMBASE, Scopus, and Clinicaltrials.gov were searched from inception to November 2017. SELECTION CRITERIA: Eligible studies included observational or randomised studies comparing vaginal and caesarean delivery in pregnancies with fetal open neural tube defects who did not undergo prenatal repair. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed abstracts and full-text articles. Outcomes were compared between vaginal and caesarean delivery and prelabour caesarean versus exposure to labour. The primary outcome was motor-anatomic level difference. Secondary outcomes included shunt requirement, sac disruption, meningitis, and ambulation at 2 years. Meta-analysis was performed and mean difference or odds ratios with 95% CI were calculated. MAIN RESULTS: Of 201 abstracts identified in the primary search, nine studies (672 women) met the eligibility criteria. Comparing vaginal and caesarean delivery, there was no significant difference in motor-anatomic level difference (mean difference -0.10, 95% CI -0.58 to 0.38; I2  = 57%). The vaginal delivery group was less likely to require a shunt or have sac disruption [odds ratio (OR) 0.37, 95% CI 0.14-0.95 and OR 0.46, 95% CI 0.23-0.90, respectively]. Comparisons by prelabour caesarean versus exposure to labour showed no significant difference in motor-anatomic level difference (OR 1.29, 95% CI 0.63-3.21) or ambulation at 2 years (OR 2.13, 95% CI 0.35-13.12). CONCLUSION: Caesarean delivery was not associated with improved neurological outcomes among fetuses with open neural tube defects. TWEETABLE ABSTRACT: Available evidence does not support routine caesarean delivery for fetuses with open neural tube defects.

Spinal Cord Stimulation in Adult Tethered Cord Syndrome: Case Report and Review of the Literature.

BACKGROUND: Spinal cord stimulation (SCS) is an evidence-based treatment for chronic neuropathic pain; however, there is a dearth of evidence investigating this modality in patients with tethered cord syndrome. CASE DESCRIPTION: We present a case of 55-year-old woman with history of lipo-myelomeningocele repair and multiple detethering surgeries who presented with chronic low back and leg pain accompanied by progressive gait dysfunction. After a successful trial, she underwent SCS paddle lead placement that resulted in decrease of her visual analog scale for pain from 9/10 to 0-2/10 as well as daily opioid intake from 90 to 199 mg morphine-equivalent doses to 40 to 60 mg morphine-equivalent doses. On last follow-up she reported 70%-85% relief of her low back and leg pain, better ambulation, and improved quality of life. CONCLUSIONS: The literature review identified 2 other case reports of SCS in tethered cord syndrome with similar improvement in pain alleviation.

Diastematomyelia and late onset presentation: a case report of a 72-year-old woman.

BACKGROUND: We would like to present the case of a 72-year-old woman, in whom diastematomyelia was surprisingly discovered when looking for an explanation for her neurological and urological complaints. Diastematomyelia is a rare disease in the group of "spinal dysraphisms," mostly discovered at birth and very rare at advanced age. The clinical pattern could be seen in the general presentation of 'tethered cord' and there are 2 types of presentation with a different treatment. CASE REPORT: In our case report the two dominant complaints were pain in the right foot and sphincter problems. Further investigations ultimately revealed diastematomyelia. Surgical resection of the septum was one of the possibilities, but because of the limited clinical impact, a conservative treatment was followed. CLINICAL REHABILITATION IMPACT: In conclusion this case shows that even at advanced age diastematomyelia can be first discovered, so attention to this rare disease stays important.

Transamniotic stem cell therapy: a novel strategy for the prenatal management of congenital anomalies.

Transamniotic stem cell therapy, or TRASCET, is an emerging therapeutic concept for the management of congenital anomalies based on the augmentation of the biological role of select populations of stem cells that already occur in the amniotic fluid, for targeted therapeutic benefit. Amniotic fluid-derived mesenchymal stem cells (afMSCs) have a central role in the enhanced ability of the fetus to repair tissue damage. This germane recent finding constitutes the biological foundation for the use of afMSCs in TRASCET. It has been shown experimentally that simple intra-amniotic delivery of afMSCs in large numbers can either elicit the repair, or significantly mitigate the effects associated with major congenital anomalies by boosting the activity that these cells normally have. For example, TRASCET can induce partial or complete coverage of experimental spina bifida by promoting the local formation of host-derived skin, thus protecting the spinal cord from further damage. In another example, it can significantly alleviate the bowel damage associated with gastroschisis, one of the most common major abdominal wall defects. Other applications involving different congenital anomalies and/or other stem cells present in the amniotic fluid in diseased pregnancies are currently under investigation in this freshly evolving facet of fetal stem cell therapy.

Practice Bulletin No. 187: Neural Tube Defects.

Neural tube defects (NTDs) are congenital structural abnormalities of the central nervous system and vertebral column. Neural tube defects may occur as an isolated malformation, in combination with other malformations, as part of a genetic syndrome, or as a result of teratogenic exposure (1). Neural tube defects are the second-most-common major congenital anomaly (2) after cardiac malformations, and their prevalence varies by geographic region, race, and environmental factors (3). Outcomes and disabilities depend on level and extent of lesion; for instance, anencephaly is incompatible with life but most infants with spina bifida will survive after surgical repair (4). Importantly, and in contrast to many other congenital abnormalities, primary prevention of NTDs is possible with folic acid. In addition, prenatal screening and diagnosis are widely available, and fetal surgery has improved outcomes for some newborns. The purpose of this document is to provide information about NTDs and make management recommendations for the pregnancy complicated by a fetal NTD.

Management of concomitant scoliosis and tethered cord syndrome in non-spina bifida pediatric population.

BACKGROUND: The management of concomitant scoliosis and tethered cord syndrome in the non-spina bifida pediatric population is challenging. In the present study, we evaluate the efficacy of different treatment modalities and propose a treatment plan for the management of affected patients. METHODS: A systematic literature review was conducted by querying the MEDLINE, PubMed, Cochrane, EMBASE, Scopus, and Web of Science databases for papers published between January 1996 and June 2016 and reporting on concomitant scoliosis and tethered cord. We excluded animal studies, non-English papers as well as papers reporting on patients with multiple concomitant intraspinal anomalies such as spina bifida. RESULTS: Out of 1993 articles, only 13 met our inclusion criteria. These 13 articles described six main management approaches: Observation, cord untethering only, cord untethering followed by deformity correction, simultaneous cord untethering and deformity correction, and deformity correction without untethering. Selection of the best approach is a function of the patient's symptomatology and Cobb angle. CONCLUSION: We propose treatment plan for the management of patients with concomitant tethered cord syndrome and spinal deformity. Asymptomatic patients can be followed conservatively and managed as scoliosis patients with no need for untethering. Surgical management in a staged fashion seems appropriate in symptomatic patients with a Cobb angle less than 35°. In these patients, deformity can improve following untethering, thus sparing the patient the risks of surgical correction of scoliosis. Staged or non-staged cord untethering and curve correction seem to be adequate in symptomatic patients with Cobb angle >35° as these patients are likely to require both untethering and deformity correction.