Continuing Education Activity

Myelomeningocele is a severe neural tube defect resulting from incomplete closure of the spinal cord during early fetal development, usually within the first month of gestation. This condition is a form of open spinal dysraphism or spina bifida aperta. Myelomeningocele is characterized by an exposed spinal cord and meninges that protrude from the vertebral column, which is evident during a physical examination. The severity of neurological impairments varies depending on the lesion's location along the spine. Higher lesions often cause motor deficits, such as paraplegia, while lower lesions may lead to sensory loss and bladder or bowel dysfunction. Risk factors for myelomeningocele include environmental exposures, maternal health issues, inadequate pre-pregnancy folic acid intake, and genetic factors, including chromosomal abnormalities such as trisomy 18 or 13.

Fetal diagnosis is typically achieved through maternal serum alpha-fetoprotein levels and ultrasonography, which reveal characteristic cranial and spinal signs. Management includes early postnatal surgical closure or prenatal repair to reduce complications such as hindbrain herniation. Treatment may also address associated hydrocephalus and Chiari II malformations through shunt placement or endoscopic surgery, aimed at preventing further neurological decline and supporting optimal development. This activity provides healthcare professionals with the knowledge and skills to recognize myelomeningoceles, conduct the recommended evaluations, and implement an interprofessional management approach to improve patient outcomes.

Objectives:

• Identify risk factors for myelomeningocele, including maternal health conditions, environmental exposures, and genetic factors.
• Implement appropriate antenatal interventions, including folic acid supplementation, to reduce the risk of myelomeningocele in high-risk pregnancies.
• Apply evidence-based practices for early postnatal surgical management or prenatal closure of myelomeningocele to reduce complications.
• Collaborate with an interprofessional healthcare team to provide holistic care that addresses the physical, psychological, and social needs of patients with myelomeningocele.

Introduction

Myelomeningocele is a severe neural tube defect caused by incomplete closure of the spinal cord during early fetal development, typically within the first month of gestation.[1][2][3] This condition is a form of open spinal dysraphism or spina bifida aperta. Myelomeningocele is characterized by an exposed spinal cord and meninges that protrude from the vertebral column, which is evident during a physical examination. In contrast, closed spinal dysraphism, or spina bifida occulta, consists of skin-covered lesions that may not be immediately noticeable except for common cutaneous findings such as hemangiomas, hypertrichosis, sacral dimples, or subcutaneous lipomas. 

Myelomeningocele is associated with significant neurological impairments that vary depending on the location of the lesion along the spine. Higher spinal lesions often result in more severe motor deficits, such as paraplegia, while lower lesions primarily cause weakness, sensory loss, and bladder or bowel dysfunction. As a result, the prognosis is generally worse if a myelomeningocele is diagnosed late or left untreated.[4][5]

Risk factors for myelomeningocele include environmental exposures, maternal health issues, inadequate pre-pregnancy folic acid intake, and genetic predispositions, including chromosomal abnormalities such as trisomy 18 or 13. Common complications include neurogenic bladder, renal problems, and concurrent conditions, such as Chiari II malformation and hydrocephalus, which worsen morbidity and mortality. Fetal diagnosis can be made through elevated maternal serum alpha-fetoprotein levels and ultrasonography, which reveal characteristic cranial and spinal signs. Management involves early postnatal surgical closure or prenatal repair to reduce complications, such as hindbrain herniation. Treatment may also address associated hydrocephalus and Chiari II malformations through shunt placement or endoscopic surgery, aimed at preventing further neurological decline and promoting optimal development.

Etiology

The etiology of myelomeningocele is often multifactorial, involving environmental, maternal, and genetic factors. Environmental factors include exposure to radiation, various types of pollution, pesticides, organic solvents, and teratogens. Maternal factors are diverse and encompass inadequate maternal nutrition, insufficient pre-pregnancy folic acid supplementation, as well as the consumption of caffeine, alcohol, and smoking. Additionally, the use of anticonvulsants and maternal conditions such as diabetes, obesity, hyperthermia, and anxiety may contribute to the risk.

Valproic acid, commonly used to treat epilepsy, migraines, and bipolar disorders, has been linked to an increased risk of spina bifida.[6] However, most cases of myelomeningocele are sporadic. Certain genetic factors may increase the risk, including chromosomal anomalies such as trisomy 18 or 13, as well as having an affected twin or first-degree relative. Specific genetic mutations affecting planar cell polarity pathways and enzymes involved in folate metabolism have also been reported in some individuals with spina bifida.[2][7]

Epidemiology

Globally, an estimated 214,000 to 322,000 cases of neural tube defects occur annually.[2][8] In the United States, the incidence of neural tube defects is approximately 0.2 per 1000 births, with an overall prevalence of 3.1 cases per 10,000 births.[9][10] The risk of neural tube defects in subsequent pregnancies increases to 2% to 3% after 1 affected pregnancy and nearly 5% to 10% after 2 affected pregnancies.[11][12] 

Maternal obesity has been associated with a 1.5- to 3-fold increased risk of spina bifida.[13][14][15] In the United States, the prevalence of neural tube defects is higher among the Hispanic population compared to African American and non-Hispanic White individuals.[16] Additionally, some studies indicate a higher incidence of neural tube defects in genetic females.[17]

Pathophysiology

Normal spinal cord development during embryogenesis occurs in 3 stages between the second and sixth week of gestation—gastrulation, primary neurulation, and secondary neurulation. By the end of the second week, the bilaminar disc consists of the epiblast and hypoblast. The primitive streak then appears, initiating gastrulation, which leads to the formation of the trilaminar disc comprising the endoderm, mesoderm, and ectoderm. Please see StatPearls' companion resource, "Embryology, Gastrulation," for more information.

The neural plate arises from a thickening of the ectoderm and is induced at the cranial end to initiate primary neurulation. The lateral edges of the neural plate elevate and fuse at the midline in a zipper-like manner, advancing in both cranial and caudal directions. The cranial neuropore usually closes by gestational day 24, followed by the caudal neuropore on day 26. Disruptions in this process can result in open spinal dysraphism, characterized by an incomplete neural tube closure, thereby exposing the spinal cord or placode.[18]

History and Physical

Neonates with myelomeningocele typically present with a sac covered by meninges, extending from the vertebral column and containing cerebrospinal fluid and neural tissue.[3] The placode is often splayed open and flattened, in contrast to the normal tubular structure of the spinal cord. The clinical presentation varies depending on the level of the lesion, with higher lesions in the thoracic spine associated with more severe deficits and a worse prognosis.[3][19] 

Patients with higher thoracic spine lesions are at greater risk of paraplegia. Lower lesions in the lumbosacral spine typically lead to weakness below the lesion and are often accompanied by bowel and bladder dysfunction. Myelomeningocele is one of the most common causes of neurogenic bladder in children. Renal, respiratory, and cardiac complications are frequent contributors to mortality in individuals with spina bifida.[19] 

The presence of associated disorders, such as Arnold-Chiari II malformation and hydrocephalus, can worsen a patient's prognosis and reduce survival rates.[19] Chiari II malformations commonly cause lower brainstem dysfunction, presenting as swallowing difficulties, a diminished gag reflex, and weak or absent crying. Please see StatPearls' companion resource, "Arnold-Chiari Malformation," for more information. Hydrocephalus often presents as cerebrospinal fluid leakage from the myelomeningocele surgical site, increased head circumference, and splaying of cranial sutures.

Common clinical features in children with myelomeningocele include pain, hypertonia, vertebral anomalies, tethered cord, and psychological or cognitive complications.[20] Moreover, children may experience delays in reaching developmental milestones, particularly with motor function. The absence of leg movements is usually due to lower motor neuron dysfunction below the lesion. However, spontaneous leg movements can occur in children due to functional neuronal conduction. These movements may be preserved and enhanced with appropriate therapeutic strategies and physiotherapy.[21] 

Sensory impairment, on the other hand, depends on the dermatomal level of the spinal lesion affecting the afferent fibers. The 2 aspects of sensation—light touch and 2-point discrimination—should be examined to localize sensory loss. These tests help differentiate between issues in the spinothalamic and dorsal column pathways. Please see StatPearls' companion resource, "How to Localize Neurologic Lesions by Physical Examination," for more information.

Evaluation

Myelomeningocele is often diagnosed during routine prenatal care. Maternal serum alpha-fetoprotein serves as an initial screening tool, with levels reaching 2.5 times higher than the median in up to 79% of pregnancies affected by open spinal dysraphism between 16 and 18 weeks of gestation.[22] Amniocentesis can serve as a confirmatory test when serum alpha-fetoprotein levels are elevated. A study found that measuring alpha-fetoprotein and acetylcholinesterase levels in amniotic fluid provides a 99% accuracy rate, with a false-positive rate of 0.34%.[23] 

Ultrasonography is a noninvasive, safe, and effective technique commonly used during second-trimester anatomy scans. This technique can help identify spinal defects and cranial anomalies associated with myelomeningocele, such as the lemon sign, which is characterized by scalloping of the frontal bones.[24] In addition, a biparietal diameter measurement below the fifth percentile has been associated with 50% of spina bifida cases. The banana sign, which is characterized by an abnormally shaped midbrain and elongated cerebellum, is another key indicator.[25]

Additional cranial features of spina bifida that are visible through ultrasonography include hydrocephalus, microcephaly, small-shaped cerebellum, and abnormal cranial bones. Additional conditions associated with myelomeningocele, such as chromosomal anomalies, dilated renal tracts, or talipes equinovarus, may also be detectable. If ultrasonography alone is insufficient for diagnosis, fetal karyotyping, computed tomography (CT), or magnetic resonance imaging (MRI) can serve as adjunctive imaging options (see Image. Myelomeningocele Detected on CT Scan).[2] MRI offers superior visualization of the spine, neural elements, and other organ systems associated with spina bifida. This technique also assesses spinal alignment, identifies different types of spinal dysraphism, and detects abnormalities within the spinal cord.[26]

Postnatal MRIs should be performed to assess for hydrocephalus, Chiari II malformations, and other brain anomalies. Common brain anomalies observed include abnormalities in the corpus callosum, colpocephaly, fusion of the thalami, small posterior fossa, aqueductal stenosis, low-lying torcula, and transverse sinuses.[27] Postnatal MRIs are crucial for surgical planning. For example, an endoscopic third ventriculostomy may be technically challenging if a large massa intermedia is present. Additionally, clinicians must carefully examine the torcula and transverse sinuses' anatomy before Chiari decompression, as these structures are often low-lying and can lead to significant hemorrhage during a suboccipital craniectomy.

Treatment / Management

Once the diagnosis of myelomeningocele is confirmed, consideration should be given to prenatal closure of the defect. After the delivery of an infant with an open spinal dysraphic defect, surgical repair should be performed within the first 48 to 72 hours to reduce the risk of wound infections and ventriculitis.[28][29][30] Until surgical repair is conducted, the patient should be kept in a prone position and receive antibiotics, and the lesion should be covered to protect it until proper closure is achieved.

Postnatal closure begins with the careful dissection of the membranous sac from the surrounding normal tissue. The neural placode is then freed, ensuring all dermal remnants are removed to reduce the risk of a dermal inclusion cyst. Once the placode is released, the pia mater is approximated to metabolize the placode. The dura is then extensively dissected from the fascia and skin, and primary closure is attempted. If primary closure is not possible, a dural patch is often used. After the dura is closed, the fascia is undermined and approximated, followed by skin closure. In some cases, relaxing incisions or extensive subcutaneous dissection may be needed to achieve a tension-free closure. Closure of very large myelomeningoceles may require either a skin flap or graft repair.[31][32][33] Interprofessional medical management is essential to prevent complications and minimize neurological deficits.[4]

Prenatal Surgery

The 2011 Management of Myelomeningocele Study (MOMS) was a prospective, randomized, multicenter trial comparing prenatal and postnatal closure of myelomeningoceles.[34] The study evaluated the following 2 primary outcomes:

• The first primary outcome was the composite of fetal or neonatal death or the need for shunt placement at 12 months of age.
• The second primary outcome was the composite of mental development and motor function at 30 months.

The results revealed significantly lower shunt placement rates in the prenatal group (40%) compared to the postnatal group (82%, P < .001) and improved mental and motor development scores at 30 months (P = .007). Furthermore, improvement in the secondary outcomes, including reduced hindbrain herniation and enhanced ambulation at 30 months, was also observed. However, prenatal surgery carries significant risks, including a higher rate of preterm births, with 13% of cases occurring before 30 weeks of gestation. Uterine thinning and dehiscence were noted during delivery. Given these risks, clinicians must provide thorough prenatal counseling, including discussing the potential need for cesarean delivery in future pregnancies.

Hydrocephalus Treatment

Despite advances in reducing the need for shunt placement through prenatal surgery, approximately 80% of children undergoing postnatal closure still require shunt placement.[35] Treatment for hydrocephalus in this population may involve shunting or endoscopic third ventriculostomy, with or without choroid plexus cauterization. Treatment criteria typically include an increase in the greatest occipitofrontal circumference crossing percentiles, worsening hydrocephalus on follow-up imaging, a head circumference above the 95th percentile, and physical examination findings such as a bulging fontanelle, sunsetting sign, or separation of cranial sutures.

The updated 1-year outcomes of the MOMS trial revealed shunt placement rates in the prenatal surgery group of 20%, 45.2%, and 79.0% for ventricular sizes less than 10 mm, 10 to 15 mm, and greater than 15 mm, respectively. In comparison, the postnatal surgery group showed shunting rates of 79.4%, 86.0%, and 87.5%, respectively, for the same ventricular size categories. These findings suggest that caution should be exercised when recommending prenatal surgery for ventricular sizes over 15 mm, as shunt placement rates are comparable between the 2 groups.[36]

Due to the high rates of shunt failure, some surgeons have shifted focus toward treating hydrocephalus with endoscopic third ventriculostomy. A recent meta-analysis comparing the success and complication rates of endoscopic third ventriculostomy with or without choroid plexus cauterization reported an overall success rate of 56%. The analysis demonstrated higher success rates when endoscopic third ventriculostomy was combined with choroid plexus cauterization compared to endoscopic third ventriculostomy alone.[37]

Chiari II Malformation Treatment 

Although Chiari II malformation is present in nearly all patients with myelomeningocele, not all require treatment. Patients may present with symptoms of brainstem dysfunction, such as dysphagia, stridor, weakness, or central sleep apnea. Before considering suboccipital decompression, it is essential to rule out hydrocephalus or issues with a functioning shunt. An analysis by Kim et al, using data from the National Spina Bifida Patient Registry (NSBPR), found that 9.15% of 4448 patients underwent Chiari decompression. The study also identified a higher likelihood of requiring decompression in patients with more rostral lesions.[38]

Differential Diagnosis

When evaluating myelomeningoceles, the differential diagnoses below should be considered.

• Terminal myelocystocele: A rare, skin-covered lesion caused by dilation of the central spinal canal at the caudal end of the vertebral column. This is a type of neural tube defect.[39]

• Sacrococcygeal teratoma: A germ cell tumor that primarily originates from multipotent stem cells of the primitive streak, typically located at the base of the coccyx.[40]

• Caudal neural tube defect: This category includes other forms of spina bifida, such as meningocele and myelocele.[40]

• Tail remnants: These are benign fibrofatty lesions typically located in the perianal area, which do not adhere to the coccygeal bone.[40]

• Rhabdomyosarcoma: A malignant soft tissue tumor originating from primitive muscle cells.[40]

• Currarino syndrome: This condition is characterized by a triad of anorectal malformation, presacral mass, and sacral bone defect. This syndrome is typically inherited in an autosomal dominant pattern.[40]

• Neuroenteric cyst: These cysts are rare, duplicated congenital lesions that result from impaired remodeling of the neurenteric canal during embryonic development, originating from the endoderm.[40][41]

• Caudal regression syndrome: This condition is characterized by sacral agenesis or hypoplasia, resulting from incomplete development of the coccygeal bone during embryogenesis.[42]

Prognosis

Delayed diagnosis of myelomeningocele significantly worsens prognosis and reduces survival rates, contributing to nearly 50% of infant deaths in resource-limited countries. Moreover, delayed and inadequate management leads to complications such as dependency, immobility, functional disability, muscle weakness, and bladder and bowel dysfunction.[19] Associated disorders, such as hydrocephalus, significantly increase the mortality risk in patients with myelomeningocele.[30][43][44] In recent years, advancements in medicine and surgery have significantly improved the overall prognosis for myelomeningocele.[45] Early surgical repair and aggressive treatments have proven effective in enhancing neurological recovery, increasing survival rates, and improving long-term outcomes for affected patients.[4][46]

Bowel dysfunction has a more significant impact on health-related quality of life than bladder dysfunction in patients with spina bifida.[47] Factors contributing to bowel dysfunction include urinary tract disorders, male sex, and obesity.[48] Improvements in bowel function can be achieved through conservative management strategies, such as retrograde and antegrade enemas. Surgical intervention is also an option; however, it is generally considered a last resort due to its high complication rates.[49]

Renal failure is one of the leading causes of mortality in patients with spina bifida. Therefore, a comprehensive urological examination should be performed after birth to prevent neurogenic bladder and renal damage. This examination includes assessing pelvic floor muscle activity and ensuring low bladder pressures. Following surgical repair, all patients should undergo clean intermittent catheterization, antimuscarinic therapy, and low-dose chemoprophylaxis. These measures help maintain low bladder pressure, prevent overactive detrusor muscle activity, and reduce the risk of urinary tract infections.[50][51]

Complications

Complications of myelomeningocele are categorized into surgical and nonsurgical types.

Surgical Complications

Surgical complications can include infections at the lesion site, bleeding, delayed wound healing, recurrent tethering of the spinal cord, and cerebrospinal fluid leakage.[52]

Nonsurgical Complications

Nonsurgical complications include:

• Neurological conditions

  • Hydromyelia
  • Arnold-Chiari II malformation
  • Hydrocephalus
  • Seizures
  • Paraplegia
  • Motor and sensory impairments
  • Neurogenic bladder and bowel dysfunction [19][53]

• Musculoskeletal conditions

  • Vertebral anomalies, such as scoliosis and muscle weakness [19]

• Physical conditions

  • Immobility
  • Delayed age of ambulation [19]

• Psychological and cognitive conditions

  • Depression
  • Suicide
  • Intellectual disability [19][54]

• Social conditions

  • Educational problems
  • Dependence
  • Unemployment [19]

• Sexual conditions

  • Erectile dysfunction
  • Impotence
  • Fertility issues [19]

• Additional conditions

  • Obesity
  • Renal failure
  • Cardiac and respiratory diseases [19]

• Latex allergy: Most patients with spina bifida are sensitive to rubber, which contains latex-allergenic proteins. Exposure to latex can trigger life-threatening anaphylaxis due to the activation of immunoglobulin E antibodies.[19][55]

Postoperative and Rehabilitation Care

Postoperative care largely depends on the type of surgical procedure performed. For neonates who undergo prenatal surgical closure of myelomeningocele and are delivered preterm, they should be placed in a specialized neonatal intensive care unit (NICU) in a latex-free environment. Coordinated medical care is essential to prevent complications related to prematurity or fetal surgery and to ensure access to appropriate medical services, ultimately optimizing patient outcomes. Although fetal surgery typically offers better outcomes than postnatal surgery, patients may face a higher risk of both intraoperative and postoperative complications.[56] Specific indications for fetal surgery include the presence of associated anomalies such as hydrocephalus, Arnold-Chiari malformation, significant thoracolumbar defects, and the absence of abnormal fetal leg movements or foot clubbing.[57]

Various postoperative complications have been reported following both prenatal and postnatal surgeries, including wound infection and dehiscence, shunt infection and failure, postoperative ileus, necrotizing enterocolitis, pneumonia, symptomatic Arnold-Chiari malformation, and complications related to kyphectomy.[52] Long-term rehabilitation care is crucial postoperatively to preserve the patient's functional neurological level and enhance their quality of life.

Preventive measures are crucial for improving musculoskeletal health through physical therapy and exercises while also reducing the risk of pressure ulcers, wound infections, deep vein thrombosis, obesity, and metabolic syndrome. Additionally, patients with hydrocephalus should have regular ophthalmology visits to screen for visual impairments and papilledema. In addition, urodynamic testing is recommended for patients experiencing any urological issues to rule out neurogenic bladder. Bowel management can be achieved by educating patients and caregivers on a reflex-triggered bowel evacuation program, dietary modifications, and appropriate use of laxatives. These strategies should be followed until the patient successfully transitions to adult care. Adult healthcare provides specialized care to promote autonomy and ensure ongoing, comprehensive patient support and care.[53]

Long-term follow-up is essential, as many patients with myelomeningocele may develop tethered cord syndrome. This condition, which can lead to neurologic, urologic, and orthopedic dysfunction, occurs in a significant number of patients. Tethered cord release is necessary in approximately 20% to 30% of cases.[58]

Deterrence and Patient Education

Myelomeningocele, the most common form of spina bifida, is characterized by a fluid-filled sac containing neural tissue that protrudes from the back. This neural tube defect results from incomplete closure of the spinal cord during the first month of pregnancy. While various factors can contribute to its development, most cases are preventable through adequate maternal nutrition and proper folic acid supplementation during pregnancy.

Patients with myelomeningocele frequently experience fluid accumulation in the brain, such as hydrocephalus, which leads to excessive pressure within the skull. For children diagnosed with hydrocephalus, shunt surgery may be required to insert a hollow tube into the brain, allowing excess fluid to drain from the ventricles. Additionally, clinicians should counsel patients to avoid latex products, as children with myelomeningocele are at risk for latex allergies.

Early surgical intervention within 24 to 48 hours after birth is crucial to reducing the risk of infection and enhancing quality of life. This approach ensures access to therapeutic services tailored to the patient's needs when combined with interprofessional care. Early surgical management has demonstrated effectiveness in improving survival rates and minimizing complications. Children with myelomeningocele often require regular medical evaluations and hospital visits to address their ongoing needs and concerns. Early medical intervention is significant for those with learning and cognitive disabilities, as it can help equip them to overcome future educational challenges.

Parents should be aware that their child may experience specific areas of disability. Therefore, individualized school programs and community services should be implemented to help children adapt to their physical abilities and limitations. Cognitive impairments in patients with spina bifida, particularly challenges with executive functioning, can improve through the implementation of tailored educational strategies in school settings. Executive functioning refers to cognitive skills such as memory, planning, attention, time management, and flexibility, which are essential for completing everyday tasks. Educational strategies to support these skills may include teaching children to write down important information, providing clocks to help them recognize time, breaking large tasks into smaller, manageable steps, reducing anxiety, and encouraging them to complete tasks independently.

Having a child with spina bifida increases the likelihood of having another affected child in subsequent pregnancies. Genetic counseling should be offered before conception to reduce the risk of another affected pregnancy. Genetic counselors can assist parents in evaluating their family history and understanding the potential risk of genetic and congenital anomalies in future pregnancies.

Recent medical advances have greatly enhanced the quality of life for children with myelomeningocele. Early identification and management of associated health issues are vital to preventing complications, particularly those impacting mobility, as well as bowel and bladder function. Prompt interprofessional medical and surgical care is critical to minimizing deficits and maximizing the potential for future improvement.

Enhancing Healthcare Team Outcomes

Effective management of myelomeningocele requires a well-coordinated interprofessional approach among healthcare providers to optimize patient-centered care, improve outcomes, enhance safety, and strengthen team performance. Clinicians, advanced practitioners, pharmacists, and other healthcare providers play critical roles in education, prevention, and treatment. Prevention of neural tube defects begins with community education and health promotion, where nurses and pharmacists inform individuals about genetic, maternal, and environmental risk factors, with a strong emphasis on folic acid supplementation. Antenatal counseling is particularly crucial for high-risk patients, focusing on regular checkups and comprehensive histories to identify risks such as diabetes, smoking, and toxin exposure. Women of childbearing age should be encouraged to start folic acid supplements at least 3 months preconception.

Interprofessional communication is crucial for delivering comprehensive care and effectively managing complications. Clinicians collaborate to address the challenges of myelomeningocele, including urinary incontinence and mobility issues, to prevent further complications such as renal failure or musculoskeletal contractures. Physical and occupational therapists play a crucial role in enhancing mobility and strength, helping to reduce disability and improve independence. Social workers, psychologists, and psychiatrists provide vital mental health support, recognizing the significant psychosocial stress often experienced due to patient dependency and the presence of special needs.

Raising awareness and reducing stigma surrounding spina bifida are essential for fostering community involvement, which is vital in enhancing quality of life and social integration. With the support of an interprofessional healthcare team, patients can achieve their educational and professional goals, making meaningful contributions to their communities. Open communication and integrated care planning are crucial for providing tailored, continuous, and patient-centered care that improves both outcomes and patient satisfaction.

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Disclosure: Torin Karsonovich declares no relevant financial relationships with ineligible companies.

Disclosure: Asayel Alruwaili declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Das declares no relevant financial relationships with ineligible companies.