Myelodysplasia and Neurogenic Bladder Dysfunction

Spinal cord and vertebra formation begin at approximately 18 days' gestation. Closure of the spinal canal begins at the cephalad end, proceeds caudally, and is complete by 35 days' gestation. The exact cause of neurospinal dysraphism is unknown, but it appears to be multifactorial. Genetic, environmental, and nutritional factors have been implicated; however, no specific etiology has been pinpointed.

An increased frequency of neural tube defects appears to occur in the offspring of mothers who had folic acid deficiency during pregnancy. On the basis of these data, the current recommended dietary allowance (RDA) of 600 μg/day of folic acid was established for women during pregnancy. ^[1]

Spina bifida is a broad term that may be used to describe a number of open defects of the spinal column. A meningocele occurs when the meningeal sac (the sac that envelops the spinal cord) extends beyond the confines of the vertebral canal but does not contain any neural elements. A myelomeningocele occurs when neural tissue (nerve roots, spinal cord tissue, or both) is included in the sac. A lipomyelomeningocele is defined by the presence of fatty tissue and neural elements within the sac.

Myelomeningoceles account for 90% of open spinal dysraphic states. The overwhelming majority of myelomeningoceles are directed posteriorly, with most defects involving the lumbar vertebrae. In decreasing order of frequency, sacral, thoracic, and cervical vertebrae are affected. In the rare case of an anteriorly directed defect, the sacral vertebrae are most commonly involved.

An Arnold-Chiari malformation is associated in 65-85% of children with a myelomeningocele. ^[2] This occurs when the cerebellar tonsils herniate through the foramen magnum and obstruct the fourth ventricle, which prevents cerebrospinal fluid (CSF) from entering the subarachnoid space. These children require shunting of the ventricles, most commonly to the peritoneum to prevent accumulation of CSF, which will cause hydrocephalus and, potentially, brain damage. A small number (~5%) of patients with myelomeningoceles do not have a neurogenic bladder, but they constitute an exception.

Congenital defects of spinal column formation that are not open defects are often termed spina bifida occulta. The lesions can be subtle, often with no obvious signs of motor or sensory denervation; however, in many patients, a cutaneous abnormality can be seen overlying the lower spine. This can vary from a dimple or a skin tag to a tuft of hair, a dermal vascular malformation, or an obvious subdermal lipoma.

Alterations may be found in the arrangement or configuration of the toes, along with discrepancies in lower-extremity muscle size and strength, weakness, or abnormal gait. Back pain and an absence of perineal sensation are common symptoms in older children. The frequency of abnormal lower urinary tract function in patients with spina bifida occulta has been reported to be as high as 40%.

Sacral agenesis, defined as the absence of two or more lower vertebral bodies, is another defect that can produce voiding dysfunction. Because perineal sensation is usually intact and lower-extremity function is normal, the only clue is often a flattened buttock and a short gluteal cleft. However, in many patients, no external signs are evident. If suspected, diagnosis is made using a lateral film of the lower spine. Even at best, only 50% of affected infants are identified in the newborn period. Children of insulin-dependent mothers have a higher risk for sacral agenesis.

The neurologic lesion produced by the dysraphism can vary widely, depending on the neural elements that have everted with the meningocele sac. The bony vertebral level correlates poorly with the neurologic lesion produced.

Additionally, different growth rates between the vertebral bodies and the elongating spinal cord can introduce a dynamic factor to the lesion. Fibrosis may surround the cord at the site of meningocele closure, and the cord can become tethered during growth. This can lead to changes in bowel, bladder, and lower-extremity function. If these are noted, investigation is warranted to exclude cord tethering.

The exact cause of spinal dysraphism is unknown, but many factors appear to be involved. Genetic, environmental, and nutritional factors have been implicated, though no specific etiology has been pinpointed.

Genetic

If myelodysplasia is present in one child in a family, the chance of having a second child with the same condition is 2-5%. The prevalence of myelodysplasia is increased in children born to mothers older than 30 years. 

In a 2019 study, whole-exome sequencing identified four loss‐of‐function variants in three genes associated with neural tube defects: MTHFR, DLC1, and ITGB1. ^[3]

Environmental

Studies of open in-vivo neural tube defects indicate that the exposed tissue in the myelomeningocele sustains secondary injury from mechanical and chemical factors during its prolonged exposure to the uterine environment. The additive effects of the congenital defect and the superimposed trauma appear to combine to determine the total neurologic deficit displayed by the infant.

Nutritional

Prevalence of neural tube defects appears to be increased in the offspring of mothers who had folic acid deficiency during pregnancy. On the basis of these data, the current RDA of 600 μg/day of folic acid has been established for women during pregnancy. ^[1]

Diabetes

Sacral agenesis appears to be associated with diabetes—specifically, with the presence of insulin during fetal development. Maternal diabetes mellitus is seen in 12-18% of patients with sacral agenesis, and 1% of children born to mothers who are insulin-dependent have the condition. The mechanism is unknown.

United States statistics

The reported prevalence of spinal dysraphism in the United States is 1 case per 1000 live births. ^[4] For unknown reasons, spinal dysraphism is more common in the eastern United States. Studies conflict regarding whether a seasonal variation occurs in prevalence. A genetic component to the disease appears to be present; if spinal dysraphism is present in one child, the chance of having a second child with the same condition is 2-5%. In addition, prevalence is increased in children born to mothers older than 30 years.

Spina bifida is the most common permanently disabling birth defect in the United States, affecting about one out of every 2758 newborns; each year, about 1427 babies are born with spina bifida in the United States. ^[5]  The Spina Bifida Association has conservatively estimated that there are 70,000 people in the United States living with this condition. ^[6] At present, its prevalence appears to be decreasing, in part because of preventive measures followed by expectant mothers before and during pregnancy, as well as antenatal testing. ^[6]

The prevalence of spina bifida occulta (myelodysplasia with a closed vertebral canal) is 1 case per 4000 live births. Prevalence of sacral agenesis in children of mothers with insulin-dependent diabetes mellitus is higher than average (1%).

International statistics

A large range in prevalence has been recorded internationally. Studies have demonstrated rates ranging from 0.12 to 4.5 cases per 1000 live births. The prevalence of spinal dysraphism appears to be lower in Asian countries.

Age-related demographics

Myelodysplasia can be detected before birth by means of antenatal ultrasonography (US). If myelodysplasia is detected antenatally, cesarean delivery may improve neurologic function by reducing the trauma caused by vaginal delivery. Neural tube defects can be suspected if amniocentesis shows increased levels of alpha-fetoprotein, but these results can be misleading, with large numbers of both false-positive and false-negative results.

In many infants, myelodysplasia is detected immediately at birth; however, spina bifida occulta may not become apparent until later in life, and voiding dysfunction may be the only sign of occult disease.

Sex-related demographics

Myelodysplasia is more common in females than in males.

Race-related demographics

A study from California demonstrated a slightly higher prevalence in children born to Hispanic mothers. ^[7]  White mothers were the second most likely to have children with myelodysplasia, followed by Black and Asian mothers.

In a study that used data from 12 state-based birth defects tracking programs from 1997-2007 to estimate the total number of pregnancies affected by spina bifida as compared with the total number of live births (ie, the prevalence of spina bifida), Hispanic women were found to be more likely to have a child affected by spina bifida than either non-Hispanic White women or non-Hispanic Black women were. ^[5] Figures for each racial/ethnic group were as follows:

• Hispanic - 3.80 per 10,000 live births
• Non-Hispanic Black or African American - 2.73 per 10,000 live births
• Non-Hispanic White - 3.09 per 10,000 live births

The prognosis for patients with myelodysplasia has improved dramatically over the past decades. As a consequence of improved neurosurgical techniques and increased availability of broad-spectrum antibiotics, far fewer infants die of central nervous system (CNS) infections and complications related to closure of the defect.

Since the introduction of intermittent catheterization (IC), incontinent urinary diversion is no longer performed with the same frequency as in the past, with the result that operative morbidity and mortality have been greatly reduced. Many patients can be treated with clean IC (CIC) alone or with adjunctive pharmacotherapy, without ever requiring surgery.

In selected patients, bladder augmentation and continence surgery may provide medical benefits and an improvement in the patient's quality of life. However, these procedures are associated with a significant risk of long-term complications.

Starting at birth and as the patient ages, parents and patients need to be educated regarding the many issues associated with living with myelodysplasia. This is a chronic condition with lifelong consequences.

Parents and patients should be taught the catheterization skill, the ability to recognize infection, the need to alleviate and prevent constipation, the importance of watching for changes in symptoms, and the facts regarding sexual issues. They should be constantly reminded of the need to adapt to new problems and the need for lifelong observation by healthcare providers. When patients are able to become involved in their own care, they should be encouraged to do so, because eventually they will be responsible for looking after themselves.

Sexuality, though not an issue in childhood, becomes a progressively more important concern as the patient ages. It has historically been ignored in individuals with myelodysplasia; nevertheless, patients with myelodysplasia have sexual encounters, and studies indicate that at least 15-20% of males are capable of fathering children and that 70% of females can conceive and carry a pregnancy to term.

Additionally, although puberty in boys with myelodysplasia appears to occur at the same age as puberty in healthy boys, menarche can begin 2 years earlier than usual in girls.

For these reasons, counseling patients in early adolescence regarding sexual development is essential.