ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Closed spinal dysraphism: Pathogenesis and types

Closed spinal dysraphism: Pathogenesis and types
Literature review current through: Jan 2024.
This topic last updated: Dec 20, 2023.

INTRODUCTION — Neural tube defects are congenital anomalies of neural development with a spectrum of clinical manifestations. They can affect the cranium or spine and are often associated with cutaneous findings [1].

The clinical manifestations of closed (occult) spinal dysraphism (see 'Terminology' below) vary widely and range from benign or asymptomatic to severe neurologic, genitourinary, gastrointestinal, or musculoskeletal anomalies. The pathogenesis and types of closed spinal dysraphism will be discussed here. The clinical presentation, evaluation, and management of these disorders are discussed in a separate topic review. (See "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management".)

TERMINOLOGY — The term "neural tube defect" refers to a broad range of congenital anomalies of neural development, with a spectrum of clinical manifestations.

Neural tube defects are the second most common congenital disability after congenital heart defects [2] and include the following:

Cranial defects, including anencephaly, exencephaly, and encephalocele. (See "Primary (congenital) encephalocele" and "Anencephaly".)

Spinal cord dysraphism refers to aberrations in the embryogenesis of the spine and spinal cord.

Open spinal dysraphism (spina bifida aperta) is characterized by a cleft in the spinal column, with herniation of the meninges (meningocele) or meninges and spinal cord (myelomeningocele) through the defect. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications" and "Myelomeningocele (spina bifida): Management and outcome".)

Closed spinal dysraphism (also known as occult spinal dysraphism or spina bifida occulta) is characterized by failure of fusion of the vertebral bodies due to abnormal fusion of the posterior vertebral arches, with unexposed neural tissue; the skin overlying the defect is intact. The more common and least severe forms consist of isolated vertebral bony defects. However, the vertebral defects may occur in association with other more severe anomalies of the spinal cord and sacral structures, such as split spinal cord malformation or various cavitary defects of the spinal cord.

RISK FACTORS — Open or closed spinal dysraphism occurs at a frequency of 0.5 to 8 cases per 1000 live births [3]. The incidence varies substantially across populations, in patterns that follow nutritional, geographic, and ethnic factors. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Prevalence'.)

Maternal risk factors for spinal dysraphism include [4]:

Folate deficiency – Folate deficiency (whether caused by dietary deficiency, folate antagonists, or genetic abnormalities of folate metabolism) has been clearly associated with open spinal dysraphism (myelomeningocele), and the benefit of folic acid supplementation has been established [5]. However, no studies have specifically addressed whether there is a relationship between folate deficiency and closed spinal dysraphism [6]. (See "Preconception and prenatal folic acid supplementation".)

Gestational diabetes – Maternal diabetes has been associated with increased incidence of the syndrome of caudal regression, but the exact mechanism remains unclear [7,8]. The incidence of caudal regression syndrome in the infants of diabetic mothers is 1 to 2 per thousand, whereas its incidence in the general population is 0.05 to 0.10 per thousand [9]. (See 'Caudal regression or sacral agenesis' below and "Infants of mothers with diabetes (IMD)", section on 'Neonatal complications'.)

Maternal obesity – The likelihood of developing spina bifida in the fetus is twofold higher in obese compared with nonobese women [4,10]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Congenital anomalies'.)

Medications – In utero exposure to certain medications, particularly antiseizure medications (eg, valproate, carbamazepine) is associated with increased risk of spinal dysraphism in the fetus [11,12]. Most studies have focused on open rather than closed spinal dysraphism. The effects of these anticonvulsant medications may be mediated through alterations in folate metabolism. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Effects of ASMs on the fetus and child'.)

NORMAL CORD DEVELOPMENT IN HUMANS — Neural tube defects can arise from abnormalities occurring during several different stages of neural tube development [1]. The embryology of neural tube development helps to explain many of the clinical findings, although the exact mechanisms underlying the development of many of these defects are not fully understood.

Notochord development — The initial phase of development of the human nervous system starts with the formation of the notochord on day 17 of gestation. The notochord then secretes signaling molecules, such as the Sonic hedgehog (SHH) protein, which induce the overlying ectoderm to differentiate into neuroectoderm (figure 1) [13]. The neuroectoderm produces precursor cells of all neural structures in the developing embryo, while the notochord itself becomes the axis of the developing vertebral column and also contributes to the formation of the nucleus pulposus of the intervertebral disc [9,14].

The endodermally-derived yolk sac is initially connected with the ectodermally-derived amnion through a primitive neurenteric canal (PNC). The PNC exists only temporarily and normally disappears to allow continued normal embryonic development. However, some inciting events may lead to persistence of adhesions between the endoderm and ectoderm, known as the accessory neurenteric canal (ANC) [15,16]. Depending on which part of the ANC fails to regress, several different clinical anomalies may result, including anomalous development of the vertebrae and spinal cord, anomalies of the gastrointestinal tract such as malrotation and neuroenteric fistula, and genitourinary malformations. The spinal dysraphic lesions include split notochord syndrome, neurenteric cysts, dorsal dermal sinus tracts and cysts, sacral meningeal cysts, and certain types of split spinal cord syndrome. (See 'Anomalies of notochord development' below.)

Primary neurulation — Primary neurulation is the process of forming a tube from the neuroectodermal tissue (figure 1) [3]. The neuroectoderm begins as a flat neural plate, which invaginates as its lateral ends elevate and come together to fuse to form the primary neural tube (PNT).

Fusion starts on day 21 of gestation [6]. The fusion begins in the middle of the neural plate and then proceeds both rostrally and caudally to form the PNT. The PNT initially has openings at both ends, known as the anterior (cranial) and posterior (caudal) neuropores. The anterior neuropore closes first at around 25 days GA, followed by the posterior neuropore at around 27 days GA (figure 2).

As the neural tube is closing, mesenchymal cells migrate between and separate the developing neural tube from the overlying ectoderm. These mesenchymal cells will form the meninges, neural arches of the vertebrae, paraspinal muscles, and dermis. In addition, some cells detach from the closing edges of the neural plate and form the neural crest cells, which have multipotent potential [17]. As the posterior neuropore closes, the process of primary neurulation is completed [3,18].

Failure of the caudal neuropore to close causes spina bifida (myelomeningocele) and spina bifida occulta, the most common neural tube defects. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications" and 'Abnormalities of primary neurulation' below.)

Secondary neurulation — The process of secondary neurulation begins by addition of a terminal segment to the caudal end of the PNT. The two segments join at approximately the level of future sacral segment 2 (S2) [19]. The terminal segment derives from the caudal cell mass (or tail bud), which is a collection of undifferentiated mesodermal cells from which arise the caudal ends of the spinal cord, notochord and GI tract, the caudal somites, the caudal neural crest cells derivatives, and the blood vessels supplying all these structures [3,18].

The cavity of the secondary neural tube (SNT) forms through two different processes. At the junction of the PNT and SNT, the cavity of the PNT grows into the SNT. However, more distally, multiple small cavities form within the SNT independently and coalesce together and with the growing PNT cavity, to form a continuous cavity that spans both the PNT and the SNT [3].

While the structures of the caudal SNT are undergoing apoptosis to form the cavity within the SNT, a thin fibrous layer remains connected to the PNT. This is a continuation of the pia mater and dura mater, known as the filum terminale [18]. The most caudal end of the spinal cord, to which the filum terminale is attached, becomes known as the conus medullaris, and its cavity becomes known as the ventriculus terminale [3,18]. The ventriculus terminale usually regress by term, but may occasionally persist, asymptomatically into adulthood [17].

Disruption of secondary neurulation leads to spinal cord anomalies that are covered by skin; they include tethered cord syndrome, terminal diplomyelia, sacrococcygeal teratomas, and sacral agenesis. (See 'Anomalies of the caudal cell mass and secondary neurulation' below.)

Junctional neurulation — Junctional neurulation refers to the sequence of events surrounding the time of caudal neuropore closure [20]. The process involves two cell populations: Sox-2 positive cells distributed as lateral stripes in continuity with the PNT and Sox-2 negative cells along the midline in continuity with the primitive streak.

As neurulation proceeds, the former cell population undergoes dorsal folding and midline fusion identical to the PNT. It fuses with the caudal end of the PNT and becomes an indistinguishable part of the PNT. The latter cell population undergoes epithelial-mesenchyme transition and moves caudally, fusing with the SNT and becoming an indistinguishable part of the SNT. In normal development, these two cell populations remain continuous with each other throughout this process, leading to intact continuity of the spinal cord.

Molecular mechanisms — While the basic structure of the spinal cord is developing through primary neurulation, the developing cord is actively undergoing ventrodorsal and rostrocaudal differentiation, guided by chemical gradients of different signaling molecules secreted by the surrounding structures. These signaling molecules control the expression of transcription factors by the developing neural cells:

FGF – Fibroblast growth factor (FGF) is secreted by the paraxial mesoderm in a decreasing caudo-rostral gradient. FGF maintains immaturity of the neural progenitor cells in the caudal area, allowing continued growth of the caudal spinal cord, while the decreasing FGF gradient in the rostral direction allows maturation of the spinal cord in a rostrocaudal sequence. This is done through differential promotion and inhibition of the expression of genes of the homeobox family (eg, Sax1), paired box family (eg, Pax6), Iroquois family (eg, Irx3) and other proneural genes (eg, Cash4).

SHH and RA – Sonic hedgehog (SHH) and retinoic acid (RA) oppose the action of FGF and promote the rostrocaudal maturation of the spinal cord. In addition, they promote the dorsoventral differentiation of the developing spinal cord, through opposite decreasing (RA) and increasing (SHH) dorsoventral gradients. The dorsal spinal cord differentiates into the alar plate under the influence of RA, while the ventral spinal cord differentiates into the basal or motor plate under the influence of SHH. This is done through the regulation of expression of yet another set of transcription factor genes belonging to the homeodomain family (such as Nkx2 and Nkx6), which are upregulated by SHH [13].

Homeobox proteins – Spatial and temporal differences in the expression of the homeobox genes are central to the process of secondary neurulation. Products of these genes regulate the growth of the SNT, the apoptotic activity that leads to cavitation and elongation of the neural tube cavity across the PNT and SNT, and the development and then regression of the fetal tail.

Prickle-1 – Prickle-1 protein, a core protein of the planar cell polarity (PCP) pathway, has been shown to play a critical role in junctional neurulation during transition from primary to secondary neurulation. Interference with its expression leads to incomplete closure of the PNT and disorganized formation of the caudal cell mass [20].

Wnt factors – The Wnt signaling pathway also plays a major role in the dorsoventral and anteroposterior axes specification [21]. Studies in mice have demonstrated that the Wnt/PCP signaling pathway controls the complex processes of caudal mass cell specification, caudo-rostral progression, and caudal neural plate closure [22]. Disruption of the Wnt/PCP pathway can lead to several abnormalities, including spina bifida.

Given the delicate interplay of molecular gradients that control the growth and differentiation of the spinal cord, it is easy to understand how minor disturbances in the microenvironment of the developing nervous system can result in congenital anomalies of varying severity.

PATHOGENESIS OF CLOSED SPINAL DYSRAPHIC ANOMALIES — The spinal dysraphic anomalies can be classified into three groups, based on the developmental stage at which they are thought to arise. Although these anomalies are discussed separately, more than one dysraphic state commonly coexists in the same patient [16,23].

The pathophysiologic explanations for these anomalies are not well established. Theories that attribute an anomaly to disruption in a specific stage of nervous system development are challenged by observations of some patients with two or more dysraphic anomalies that are thought to originate at different stages of nervous system development [24].

It is possible that such anomalies coexist because a disruption at one stage of neural development also disrupts later stages of development.

Alternatively, the anomalies may have a common genetic or environmental trigger.

However, it is possible that the proposed pathophysiology does not apply to humans because the supporting data for these hypotheses largely come from studies of mammals and non-mammalian vertebrates, especially mice and chick embryos.

ANOMALIES OF NOTOCHORD DEVELOPMENT — Each of the anomalies in this category are thought to be caused by persistence of the accessory neurenteric canal (ANC) connecting the endoderm and ectoderm during development of the notochord.

Depending on whether and which part of the ANC is resorbed, several different clinical anomalies may result, including anomalous development of the vertebrae and spinal cord, anomalies of the gastrointestinal tract such as malrotation and neuroenteric fistula, and genitourinary malformations:

Persistence of the anterior part of the ANC

Neurenteric cysts — Neurenteric cysts result from persistence of the anterior part of the ANC, with resorption of its dorsal part [16,25]. As expected, these malformations are usually associated with a split notochord [26]. The persistence of such a cyst with its connection to the intestines may lead to intestinal anomalies such as malrotation or even duplication [16].

Persistence of the intermediate part of the ANC

Split notochord syndrome — The split notochord syndrome results from persistence of the intermediate part of the ANC, which forces the notochord to follow an abnormal development pattern around the adhesion, resulting in a split notochord [25]. This may lead to anomalous development of the spinal cord and surrounding mesoderm, with extensive defects and an open dysraphic state [25], and abnormal vertebral bodies [16,27].

The vertebral defects associated with split notochord syndrome range in severity from a mere vertebral cleft or bifid vertebrae (which when it affects the posterior vertebral element is referred to as spina bifida occulta), to hemivertebrae, block or fused vertebrae (such as in the Klippel-Feil anomaly), hypertrophic or hyperplastic vertebrae and butterfly vertebrae, to absent vertebrae, and in the most severe form may also lead to partial or total sacral agenesis [6,9,16].

Total sacral agenesis is usually associated with extensive defects in all structures that arise from the caudal cell mass and is known as the caudal regression syndrome. (See 'Caudal regression or sacral agenesis' below.)

Split spinal cord malformation — Split spinal cord malformation (SSCM) is the current term to describe anomalies in which there is splitting or duplication of the spinal cord. Terms used in the past literature include diastematomyelia, diplomyelia, pseudo-diplomyelia and dimyelia; these terms were used inconsistently and at times interchangeably.

SSCM is thought to arise when the persistent intermediate part of the ANC causes the neural placode to split and not just the notochord. SSCM may present at any age and is 1.3 to 6 times more frequent in females as compared with males.

SSCM is divided into two types [28]. The percentage of type I SSCM reported in the literature is highly variable, ranging from 30 to 80 percent [16,29]:

In type I SSCM, previously called diastematomyelia, each hemicord has a full thecal sac and meningeal covering, and they are separated by a bony spur, forming a double spinal canal. This is thought to occur when there are precursor meningeal cells in the ANC around which the spinal cord splits. These meningeal cells contribute to the formation of the medial aspect of the thecal sac around the two developing hemicords, while the lateral aspect of the sac develops normally around the two hemicords. The ANC persists and forms the bony ridge between the two thecal sacs. The bony spur between the hemicords may be perfectly median, dividing the cord into two symmetric hemicords, or it may be asymmetric, dividing it into a larger functional cord, and a smaller non-functional one. An asymmetric spur has been reported in 10 to 50 percent of SSCM I cases in the literature. The hemicords usually join below the level of the spur, but this is not always the case.

In type II SSCM, often called diplomyelia in older terminology, the two hemicords are surrounded by one thecal sac and there is a single spinal canal. The hemicords are generally symmetrical and may be separated by a fibrous band which is the length of one or two vertebral segments. This pattern is thought to occur when no meningeal precursor cells are incorporated in the ANC. In this case, the ANC tends to disappear completely, or persists only as the fibrous tract between the hemicords.

A different embryological theory has been proposed to explain a terminal SSCM type II anomaly (or terminal diplomyelia); this anomaly is thought to be caused by abnormal secondary neurulation and is discussed below. (See 'Terminal diplomyelia' below.)

Sacral meningeal cysts, meningoceles, and myelocystoceles — Sacral cysts are thought to arise when the ANC partially resorbs both ventrally and dorsally, leaving only a cyst-like structure with no connection to the intestines or skin. This cyst-like structure is incorporated in the mesenchyme destined to form the sacrum, forming a sacral cyst [16,25]. The spinal meninges with or without the terminal spinal cord can then herniate into this defect, forming a sacral meningocele [25,30].

Sacral meningeal cysts usually communicate freely with the subarachnoid space and are known as perineural or Tarlov cysts [9]. Most of these cysts are asymptomatic; cysts that do not communicate with the subarachnoid space are more likely to cause symptoms [31].

In a study of 500 consecutive lumbar magnetic resonance imaging studies obtained for different reasons, sacral cysts were noted to occur in five percent of imaged patients [32].

Persistence of the posterior part of the ANC

Dorsal dermal sinus tracts and cysts — If the dorsal part of the ANC persists, the remaining cyst keeps its ectodermal connection, leading to dorsal dermal sinus tracts or cysts (image 1), with their associated cutaneous anomalies including lumbosacral infantile hemangiomas and sacrococcygeal dimples or pits (table 1). This pattern is known as dysraphic cutaneous syndrome [16,33].

The dorsal dermal sinuses occur with a frequency of around 1 in 2500 live births and are most commonly found in the lumbosacral area (around 10 percent and 1 percent occurring in the thoracic and cervical areas, respectively). These cutaneous lesions are often associated with spina bifida occulta, with the bifid vertebra lying at the level of entry of the tract into the dural space [23]. (See 'Isolated vertebral defects' below.)

Dysraphic cutaneous syndrome typically has one or more of three clinical presentations:

Midline dimple – Most commonly, they come to medical attention because of a midline dimple, pit or hemangioma (picture 1), usually above the top of the intergluteal fold. (See "Assessment of the newborn infant", section on 'Trunk and spine'.)

Meningitis – Some patients come to medical attention when they develop meningitis; the infection tends to be caused by unusual organisms as compared with causes of bacterial meningitis in other settings. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)

Neurologic deficit – Other patients present with a neurologic deficit, which often is progressive [23]. The neurologic deficit can be due to different causes. Commonly it is due to cord tethering, either by the tract itself, or by an associated inelastic filum [6,23]. Spinal cord compression also may be caused by inclusion masses, which are associated with dorsal dermal sinuses in 35 to 55 percent of cases. These masses usually are dermoid, epidermoid, or teratoid tumors.

The neurologic deficit can also be due to an infection such as an epidural abscess compressing the cord. The tract of the dorsal dermal sinus may terminate anywhere from outside the vertebral column, to the extradural, subdural, and subarachnoid spaces, or even on the nerve roots, filum, or cord itself. Therefore, probing of the sinus or a fistulogram should never be performed [23].

Limited dorsal myeloschisis — Limited dorsal myeloschisis (LDM) consists of a persistent fibroneural stalk between the spinal cord and the inner part of the skin, through an occult dysraphic lesion [34]. When the persistent fibroneural stalk extends through the spinal cord, it can lead to split cord formation [35]. If the LDM lesion is proximal and hence not epithelial-lined, there typically is an associated distal congenital dermal sinus, which is epithelial-lined [36]. LDM is also commonly associated with other anomalies, such as lipomyelomeningocele, tethered cord, lipoma, congenital heart disease, and teratoma [37].

LDM was previously termed meningocele manqué [38]. Most contemporary reports use the term LDM since studies using various immunohistochemical techniques have found no evidence of meningeal tissue in the tracts tethering the cord to the skin [39].

However, there may be a subpopulation of patients with subdural tethering of the cord to the internal surface of the skin who cannot be appropriately classified into any other category, and for these patients, the term meningocele manqué may still be the best nomenclature [40].

ABNORMALITIES OF PRIMARY NEURULATION

Syringohydromyelia — Two forms of syringohydromyelia are defined.

The embryonic form consists of abnormal dilatation of the central canal of the spinal cord, with thinning and expansion of the roof plate, and absence or near-absence of mesenchymal tissue between the roof plate and the overlying ectoderm, causing a gap in the posterior vertebral arches (picture 2) [17].

By contrast, the hydromyelia that develops at the fetal stage or later does not affect mesenchymal tissue development and is usually associated with an intact vertebral column. It may be asymptomatic and is sometimes identified only incidentally in otherwise healthy adults. In this latter case, it is termed "idiopathic localized hydromyelia" [41].

This lesion could result from excessive secretion of CSF into the spinal canal or may also be caused by acquired lesions of the spinal cord, including infection, tumor, or trauma. Similar lesions are also seen as part of a syndrome with other associated abnormalities, not related to the development of the syringohydromyelia per se (image 2). (See "Disorders affecting the spinal cord", section on 'Syringomyelia'.)

Isolated vertebral defects — Isolated vertebral defects are the most common form of closed spinal dysraphism. They are characterized by a failure of fusion of the vertebral bodies dorsal to the spinal cord. This finding is sometimes described as closed spinal dysraphism (or spina bifida occulta). However, because these terms are also used to refer to the many different types of spinal dysraphic anomalies described in this topic review, we prefer to describe these more specifically as "vertebral defects" or "defects in the posterior vertebral arches."

Radiographic findings in addition to the defect in the posterior vertebral arches may include widening of the spinal canal, fusion of the vertebral bodies, and fused or malformed laminae. Minor abnormalities of the overlying skin are common, including nevi, dermal sinus or dimple, hemangioma, underlying lipoma, or a hirsute area (table 1) [42]. (See "Assessment of the newborn infant", section on 'Sacral dimple'.)

When this finding occurs in isolation, it is usually incidental and clinically asymptomatic. If the vertebral defect is associated with pain or neurologic deficits, this usually indicates that there is an associated spinal cord anomaly, such as a cyst or tethered cord. The diagnosis and management of these issues are discussed elsewhere. (See "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management", section on 'Evaluation and diagnosis'.)

Because the normal neural arch ossification is not complete until the age of two to three years, an incompletely ossified neural arch in a child younger than three years of age should not be mistaken for spina bifida occulta [43]. In addition, an incompletely ossified dorsal neural arch is a normal variant seen in 20 to 30 percent of healthy individuals [6]. This type of vertebral variation is not considered a form of spinal dysraphism, although it is described as spina bifida occulta by a few authors.

When the overlying skin is not intact, the meninges and/or spinal cord will herniate through the defect. This is termed open spina bifida, spina bifida aperta, or spina bifida cystica [17,44]. If only meninges are herniated, this forms a meningocele, while if both meninges and spinal cord herniate through the defect, a myelomeningocele is formed. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications".)

Spinal lipomas and teratomas — Spinal lipomas (image 3) occur in around 1 in 4000 live births [45]. These tumors probably arise from abnormal mesodermal cells that failed to normally migrate and remained trapped between the roof plate and the ectoderm [17,46]. They often contain multiple types of tissue, so they can be considered complex teratomas [47].

Progressive neurological dysfunction in patients with lumbosacral lipomas may be caused by compression of the spinal cord by the lipoma, or by tethered spinal cord, which frequently coexists in the same patient. In addition, most patients with spinal lipomas have malformations of the spinal cord and its roots (68 percent) or vertebral column (spina bifida, 80 percent; sacral agenesis, 25 percent) [47].

Most patients have cutaneous stigmata, such as a subcutaneous lump, dermal sinus or lumbosacral hemangioma (picture 1). A significant minority have associated anomalies of the urogenital or gastrointestinal systems. (See "Infantile hemangiomas: Evaluation and diagnosis", section on 'LUMBAR syndrome'.)

ANOMALIES OF JUNCTIONAL NEURULATION — There are a few case reports of junctional neural tube defects [48-50]. These anomalies result in a fully functional primary neural tube (PNT) and fully functional secondary neural tube (SNT) that are anatomically and functionally separate from each other. The PNT and SNT are connected by a non-neural mesenchymal fibrous band, with varying degrees of dysfunction of the structures arising from the caudal cell mass.

ANOMALIES OF THE CAUDAL CELL MASS AND SECONDARY NEURULATION — This group of anomalies are thought to result from abnormal development of the caudal cell mass (caudal eminence), and hence of secondary neurulation [51]. As a result, this group of anomalies is less likely to be associated with skin stigmata, because primary neurulation and ectodermal development is usually complete by the time that the caudal cell mass develops [6].

In other cases, these anomalies may be a secondary consequence of abnormal notochord development, and are found with anomalies from that stage of development, including skin stigmata [14]. (See 'Anomalies of notochord development' above.)

Tethered cord syndrome — Tethered cord syndrome (TCS) is stretch-induced dysfunction of the caudal spinal cord and conus, caused by attachment of the filum terminale to inelastic structures caudally (image 4). TCS may occur independently or in association with any of the other dysraphic lesions, whether open or closed [6]. The filum terminale is normally viscoelastic in nature and serves to dampen movements of the spine during flexion and extension, without applying undue traction to the moving spinal cord [52]. In TCS, the spinal cord is attached to abnormally inelastic structures caudally, such as a fibrous or fat-infiltrated filum, tumor, meningoceles or myelomeningoceles, scars, or septa (as seen in SSCM).

When TCS is not secondary to another abnormality, it is usually due to anomalous regression of the human tail, part of the normal involution of the caudal cell mass [6,52]. This has been termed "retained medullary cord" since a cord-like structure persists from the conus to the dural cul-de-sac. Though this is not due to another underlying etiology, it can still be associated with other dysraphic features [53].

This causes the caudal portion of the spinal cord to stretch between the point of tethering and the dentate ligaments that fix the cord proximally [54]. Progressive dysfunction occurs because of repeated extension or flexion of the spine. The progressive dysfunction has also been attributed to differential growth of the vertebral column as compared with the spinal cord [54], but there is controversy on this point [52].

In the short term, stretching of the spinal cord causes biochemical and electrophysiological changes that are still reversible if the stretch is released surgically [54,55]. The severity of the biochemical and electrophysiological abnormalities is found to be proportionate to the degree of stretching in animal models and proportionate to the severity of the clinical symptoms in humans. In the long term, the stretching of the spinal cord leads to neuronal degeneration and regeneration, and the neurological deficits may become irreversible [54,56].

In toddlers and children, tethered cord syndrome typically presents with progressive motor and sensory dysfunction, which may include gait abnormalities and loss of bladder control [57]. Older children and adolescents are more likely to complain of pain in the lumbosacral region, perineum, and legs. Some patients have associated orthopedic problems including progressive scoliosis. (See "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management", section on 'Tethered cord syndrome'.)

Terminal diplomyelia — Terminal diplomyelia refers to duplication or splitting of the terminal spinal cord. This anomaly is not always symptomatic, and may be incidentally seen in otherwise healthy children [3]. Terminal diplomyelia is considered to be an anomaly of secondary neurulation, caused by abnormal cavitation in the SNT. The multiple cavities do not coalesce with each other normally, resulting in persistence of more than one cavity which leads to canal duplication or forking, affecting the conus medullaris, ventriculus terminalis and filum terminalis.

By contrast, split spinal cord malformation (SSCM) occurs rostral to the terminal spinal cord, and the spinal cord above and below the lesion is normal. SSCM is thought to be caused by faulty primary neurulation [16]. (See 'Split spinal cord malformation' above.)

Sacrococcygeal teratomas — Teratomas are tumors that comprise tissues of all three germ layers or that include tissues foreign to the neoplasm's site of origin. Sacrococcygeal teratomas are thought to arise from pluripotent somatic stem cells within the caudal cell mass that do not differentiate normally due to an interruption of the normal signaling pathways [58].

Sacrococcygeal teratomas are the most common neoplasm in neonates, with a birth prevalence of 1 per 27 000 live births [59]. They occur more commonly in females than males with a ratio of approximately 3:1 [60,61]. Sacrococcygeal teratomas recur after resection in approximately 10 percent of patients; tumors that have immature histology or that arise after birth are more likely to have early malignant transformation [62,63]. In one case series, the cumulative risk of developing a malignancy by age three years was more than 60 percent [63]. (See "Sacrococcygeal teratoma".)

Fetuses with a sacrococcygeal teratoma may require delivery by cesarian section, either because the teratoma is large enough to hinder vaginal delivery [58] or because of the associated obstetric complications such as polyhydramnios, preeclampsia, spotting, or rapid weight gain. With the advent of routine ultrasonography at 16 to 18 weeks gestation, many of the tumors are diagnosed in otherwise asymptomatic pregnancies.

The appearance of fetal hydrops and/or placentomegaly carries a negative prognosis; once these tumors become symptomatic, the fetal mortality rate increases significantly due to high-output cardiac failure, and fetal surgery is sometimes considered [64-67].

Caudal regression or sacral agenesis — Caudal regression syndrome consists of a spectrum of structural defects of the caudal region, including incomplete development of the sacrum and sometimes of the lumbar vertebrae. The disorder may be associated with either closed or open spinal dysraphism, and most patients also have cord tethering [7]. This syndrome, whether associated with either occult or open spinal dysraphism, seems to occur with increased incidence in children of mothers with insulin-dependent diabetes, although the mechanisms for this association are not clear [9,68,69]. (See "Infants of mothers with diabetes (IMD)", section on 'Neonatal complications'.)

If the caudal regression syndrome is associated with closed dysraphism, the bony lesion is at a low spinal level. This pattern is probably caused by abnormal development of the caudal cell mass affecting all tissues that derive from it, including the neural, gastrointestinal, urogenital and musculoskeletal tissues of the caudal vertebral column and lower extremities [7,68].

Caudal regression syndrome may also be associated with high bony lesions and an open dysraphic state, with a spinal meningocele, and truncation of the spinal cord. In this case, it is probably caused by abnormal notochord development [6,9,16].

The clinical presentation of caudal regression syndrome is highly variable, depending on the level of the spinal lesion. Affected infants may appear to have a small pelvis, small flat buttocks, and bilateral buttock dimples with a short intergluteal cleft. They usually also have neurogenic bladder, and variable degrees of limb deformity, depending on the level of the defect (picture 3 and picture 4). Caudal regression may also present as part of a syndrome, in which case a wide variety of organ systems can be affected (table 2). These syndromes include [6,68,70]:

VACTERL (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal fistula, Renal and Limb anomalies). (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Tracheal atresia'.)

OEIS (Omphalocele, cloacal Exstrophy, Imperforate anus, Spinal malformation). (See "Body stalk anomaly and cloacal exstrophy: Prenatal diagnosis and management", section on 'Cloacal exstrophy'.)

The Currarino syndrome, which consists of a sacral vertebral defect, a presacral mass (such as an anterior sacral meningocele or presacral teratoma), and anorectal malformations [25,68]. In patients with presacral teratomas, malignant transformation rarely occurs [63,68]. Currarino syndrome is autosomal dominant in inheritance, localizes to 7q36, and mutations of a homeobox gene have been identified in certain families [1].

The term caudal regression syndrome is sometimes used to include sirenomelia, which consists of sacral agenesis and fused lower extremities (causing the fetus to resemble a mermaid). Sirenomelia is thought to be caused by abnormal shunting of the vitelline artery, causing vascular steal from the abdominal aorta and lower extremity [71]. Whether these disorders have distinct pathogenesis remains controversial [72], though it is more likely that they are different disorders [8].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Congenital malformations of the central nervous system".)

SUMMARY

Terminology – Closed spinal dysraphism (also known as spina bifida occulta) refers to failure of fusion of the vertebral bodies due to abnormal fusion of the posterior vertebral arches, with unexposed neural tissue. The more common and least severe forms consist of isolated vertebral bony defects. However, the vertebral defects may occur in association with other more severe anomalies of the spinal cord and sacral structures. (See 'Terminology' above.)

Risk factors – Risk factors include folate deficiency, maternal diabetes, maternal obesity, and some medications. (See 'Risk factors' above.)

Split spinal cord malformation (SSCM) – SSCM describes anomalies where there is splitting or duplication of the spinal cord. In type I SSCM, each hemicord has a full thecal sac and meningeal covering, and they are separated by a bony spur, forming a double spinal canal. In type II SSCM, the two hemicords are surrounded by one thecal sac and there is a single spinal canal. (See 'Split spinal cord malformation' above.)

Isolated vertebral defects – Isolated vertebral defects are the most common form of closed spinal dysraphism. Associated findings may include minor abnormalities of the overlying skin, including nevus, dermal sinus or dimple, an underlying lipoma, or a hirsute area. These findings may be asymptomatic and identified incidentally or may be associated with pain or neurologic deficits, in which case there is likely to be an additional spinal cord anomaly, such as cysts or a tethered cord. (See 'Isolated vertebral defects' above.)

Tethered cord – Tethered cord syndrome (TCS) is stretch-induced dysfunction of the caudal spinal cord and conus, caused by attachment of the filum terminale to inelastic structures caudally. TCS may occur in isolation or in association with other dysraphic lesions. Symptoms of tethered cord syndrome may include progressive motor and sensory dysfunction; sphincteric dysfunction; pain in the lumbosacral region, perineum, and legs; or progressive scoliosis. (See 'Tethered cord syndrome' above.)

Terminal diplomyelia – Terminal diplomyelia refers to duplication or splitting of the terminal spinal cord. This anomaly is not always symptomatic and may be incidentally seen in otherwise healthy children. (See 'Terminal diplomyelia' above.)

Caudal regression – Caudal regression syndrome consists of a spectrum of structural defects of the caudal region, including incomplete development of the sacrum and sometimes of the lumbar vertebrae. An increased frequency of caudal regression has been noted in infants of diabetic mothers. Genetic contributors also seem likely, as suggested by the association of caudal regression with several genetic syndromes. (See 'Caudal regression or sacral agenesis' above.)

Management – The evaluation and management of suspected closed spinal dysraphism is discussed in a separate topic review. (See "Closed spinal dysraphism: Clinical manifestations, diagnosis, and management".)

  1. Dias M, Partington M, SECTION ON NEUROLOGIC SURGERY. Congenital Brain and Spinal Cord Malformations and Their Associated Cutaneous Markers. Pediatrics 2015; 136:e1105.
  2. Detrait ER, George TM, Etchevers HC, et al. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol 2005; 27:515.
  3. Saitsu H, Yamada S, Uwabe C, et al. Development of the posterior neural tube in human embryos. Anat Embryol (Berl) 2004; 209:107.
  4. Donnan J, Walsh S, Sikora L, et al. A systematic review of the risks factors associated with the onset and natural progression of spina bifida. Neurotoxicology 2017; 61:20.
  5. Betteridge KJ. Comparative aspects of conceptus growth: a historical perspective. Reproduction 2001; 122:11.
  6. Michelson DJ, Ashwal S. Tethered cord syndrome in childhood: diagnostic features and relationship to congenital anomalies. Neurol Res 2004; 26:745.
  7. Estin D, Cohen AR. Caudal agenesis and associated caudal spinal cord malformations. Neurosurg Clin N Am 1995; 6:377.
  8. Boulas MM. Recognition of caudal regression syndrome. Adv Neonatal Care 2009; 9:61.
  9. Diel J, Ortiz O, Losada RA, et al. The sacrum: pathologic spectrum, multimodality imaging, and subspecialty approach. Radiographics 2001; 21:83.
  10. Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA 2009; 301:636.
  11. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324:674.
  12. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77:193.
  13. Lobjois V, Benazeraf B, Bertrand N, et al. Specific regulation of cyclins D1 and D2 by FGF and Shh signaling coordinates cell cycle progression, patterning, and differentiation during early steps of spinal cord development. Dev Biol 2004; 273:195.
  14. Qi BQ, Beasley SW, Frizelle FA. Evidence that the notochord may be pivotal in the development of sacral and anorectal malformations. J Pediatr Surg 2003; 38:1310.
  15. Proctor MR, Bauer SB, Scott RM. The effect of surgery for split spinal cord malformation on neurologic and urologic function. Pediatr Neurosurg 2000; 32:13.
  16. Schijman E. Split spinal cord malformations: report of 22 cases and review of the literature. Childs Nerv Syst 2003; 19:96.
  17. Ikenouchi J, Uwabe C, Nakatsu T, et al. Embryonic hydromyelia: cystic dilatation of the lumbosacral neural tube in human embryos. Acta Neuropathol 2002; 103:248.
  18. Economides KD, Zeltser L, Capecchi MR. Hoxb13 mutations cause overgrowth of caudal spinal cord and tail vertebrae. Dev Biol 2003; 256:317.
  19. Müller F, O'Rahilly R. The development of the human brain, the closure of the caudal neuropore, and the beginning of secondary neurulation at stage 12. Anat Embryol (Berl) 1987; 176:413.
  20. Dady A, Havis E, Escriou V, et al. Junctional neurulation: a unique developmental program shaping a discrete region of the spinal cord highly susceptible to neural tube defects. J Neurosci 2014; 34:13208.
  21. Hikasa H, Sokol SY. Wnt signaling in vertebrate axis specification. Cold Spring Harb Perspect Biol 2013; 5:a007955.
  22. López-Escobar B, Caro-Vega JM, Vijayraghavan DS, et al. The non-canonical Wnt-PCP pathway shapes the mouse caudal neural plate. Development 2018; 145.
  23. Ackerman LL, Menezes AH, Follett KA. Cervical and thoracic dermal sinus tracts. A case series and review of the literature. Pediatr Neurosurg 2002; 37:137.
  24. Solanki GA, Evans J, Copp A, Thompson DN. Multiple coexistent dysraphic pathologies. Childs Nerv Syst 2003; 19:376.
  25. Ilhan H, Tokar B, Atasoy MA, Kulali A. Diagnostic steps and staged operative approach in Currarino's triad: a case report and review of the literature. Childs Nerv Syst 2000; 16:522.
  26. Ebisu T, Odake G, Fujimoto M, et al. Neurenteric cysts with meningomyelocele or meningocele. Split notochord syndrome. Childs Nerv Syst 1990; 6:465.
  27. van Ramshorst GH, Lequin MH, Mancini GM, van de Ven CP. A case of split notochord syndrome: a child with a neuroenteric fistula presenting with meningitis. J Pediatr Surg 2006; 41:e19.
  28. Tahir Z, Craven C. Gastrulation and Split Cord Malformation. Adv Tech Stand Neurosurg 2023; 47:1.
  29. Cheng B, Li FT, Lin L. Diastematomyelia: a retrospective review of 138 patients. J Bone Joint Surg Br 2012; 94-B:365.
  30. Gupta DK, Mahapatra AK. Terminal myelocystoceles: a series of 17 cases. J Neurosurg 2005; 103:344.
  31. Davis SW, Levy LM, LeBihan DJ, et al. Sacral meningeal cysts: evaluation with MR imaging. Radiology 1993; 187:445.
  32. Paulsen RD, Call GA, Murtagh FR. Prevalence and percutaneous drainage of cysts of the sacral nerve root sheath (Tarlov cysts). AJNR Am J Neuroradiol 1994; 15:293.
  33. Sewell MJ, Chiu YE, Drolet BA. Neural tube dysraphism: review of cutaneous markers and imaging. Pediatr Dermatol 2015; 32:161.
  34. Pang D, Zovickian J, Oviedo A, Moes GS. Limited dorsal myeloschisis: a distinctive clinicopathological entity. Neurosurgery 2010; 67:1555.
  35. Izci Y, Kural C. Limited Dorsal Myeloschisis with and without Type I Split Cord Malformation: Report of 3 Cases and Surgical Nuances. Medicina (Kaunas) 2019; 55.
  36. Lee JY, Park SH, Chong S, et al. Congenital Dermal Sinus and Limited Dorsal Myeloschisis: "Spectrum Disorders" of Incomplete Dysjuction Between Cutaneous and Neural Ectoderms. Neurosurgery 2019; 84:428.
  37. Batista Cezar-Junior A, Faquini IV, Frank K, et al. Limited dorsal myeloschisis with a contiguous stalk to human tail-like cutaneous appendage, associated with a lipoma of conus medullaris: A case report. Int J Surg Case Rep 2020; 71:303.
  38. Lassman LP, James CC. Meningocoele manqué. Childs Brain 1977; 3:1.
  39. Rajpal S, Salamat MS, Tubbs RS, et al. Tethering tracts in spina bifida occulta: revisiting an established nomenclature. J Neurosurg Spine 2007; 7:315.
  40. Schmidt C, Bryant E, Iwanaga J, et al. Meningocele manqué: a comprehensive review of this enigmatic finding in occult spinal dysraphism. Childs Nerv Syst 2017; 33:1065.
  41. Jinkins JR, Sener RN. Idiopathic localized hydromyelia: dilatation of the central canal of the spinal cord of probable congenital origin. J Comput Assist Tomogr 1999; 23:351.
  42. Guggisberg D, Hadj-Rabia S, Viney C, et al. Skin markers of occult spinal dysraphism in children: a review of 54 cases. Arch Dermatol 2004; 140:1109.
  43. Oh, BC, Wang, MY. Cervical Anatomy and Surgical Approaches. In: Surgery of the Pediatric Spine, Kim, DH, et al (Eds), Thieme Medical Publishers, Inc., New York 2008. p.95.
  44. Kinsman S. Spina bifida. In: Neurobiology of Disease, Gilman S (Ed), Elsevier Academic Press, 2007. p.611.
  45. Tubbs RS, Wellons JC 3rd, Oakes WJ. Occipital encephalocele, lipomeningomyelocele, and Chiari I malformation: case report and review of the literature. Childs Nerv Syst 2003; 19:50.
  46. Catala M. Embryogenesis. Why do we need a new explanation for the emergence of spina bifida with lipoma? Childs Nerv Syst 1997; 13:336.
  47. Pierre-Kahn A, Zerah M, Renier D, et al. Congenital lumbosacral lipomas. Childs Nerv Syst 1997; 13:298.
  48. Eibach S, Moes G, Hou YJ, et al. Unjoined primary and secondary neural tubes: junctional neural tube defect, a new form of spinal dysraphism caused by disturbance of junctional neurulation. Childs Nerv Syst 2017; 33:1633.
  49. Schmidt C, Voin V, Iwanaga J, et al. Junctional neural tube defect in a newborn: report of a fourth case. Childs Nerv Syst 2017; 33:873.
  50. Florea SM, Faure A, Brunel H, et al. A case of junctional neural tube defect associated with a lipoma of the filum terminale: a new subtype of junctional neural tube defect? J Neurosurg Pediatr 2018; 21:601.
  51. Pang D. Sacral agenesis and caudal spinal cord malformations. Neurosurgery 1993; 32:755.
  52. Tubbs RS, Oakes WJ. Can the conus medullaris in normal position be tethered? Neurol Res 2004; 26:727.
  53. Morioka T, Murakami N, Kanata A, et al. Retained medullary cord with sacral subcutaneous meningocele and congenital dermal sinus. Childs Nerv Syst 2020; 36:423.
  54. Yamada S, Won DJ, Siddiqi J, Yamada SM. Tethered cord syndrome: overview of diagnosis and treatment. Neurol Res 2004; 26:719.
  55. Yamada S. Tethered cord syndrome in adults and children. Neurol Res 2004; 26:717.
  56. Yamada S, Knerium DS, Mandybur GM, et al. Pathophysiology of tethered cord syndrome and other complex factors. Neurol Res 2004; 26:722.
  57. Hertzler DA 2nd, DePowell JJ, Stevenson CB, Mangano FT. Tethered cord syndrome: a review of the literature from embryology to adult presentation. Neurosurg Focus 2010; 29:E1.
  58. Flake AW. Fetal sacrococcygeal teratoma. Semin Pediatr Surg 1993; 2:113.
  59. Swamy R, Embleton N, Hale J. Sacrococcygeal teratoma over two decades: birth prevalence, prenatal diagnosis and clinical outcomes. Prenat Diagn 2008; 28:1048.
  60. Rescorla FJ, Sawin RS, Coran AG, et al. Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 1998; 33:171.
  61. Schropp KP, Lobe TE, Rao B, et al. Sacrococcygeal teratoma: the experience of four decades. J Pediatr Surg 1992; 27:1075.
  62. De Backer A, Madern GC, Hakvoort-Cammel FG, et al. Study of the factors associated with recurrence in children with sacrococcygeal teratoma. J Pediatr Surg 2006; 41:173.
  63. Dirix M, van Becelaere T, Berkenbosch L, et al. Malignant transformation in sacrococcygeal teratoma and in presacral teratoma associated with Currarino syndrome: a comparative study. J Pediatr Surg 2015; 50:462.
  64. Perrelli L, D'Urzo C, Manzoni C, et al. Sacrococcygeal teratoma. Outcome and management. An analysis of 17 cases. J Perinat Med 2002; 30:179.
  65. Wilson RD. Prenatal evaluation for fetal surgery. Curr Opin Obstet Gynecol 2002; 14:187.
  66. Wilson RD, Hedrick H, Flake AW, et al. Sacrococcygeal teratomas: prenatal surveillance, growth and pregnancy outcome. Fetal Diagn Ther 2009; 25:15.
  67. Gucciardo L, Uyttebroek A, De Wever I, et al. Prenatal assessment and management of sacrococcygeal teratoma. Prenat Diagn 2011; 31:678.
  68. Lynch SA, Wang Y, Strachan T, et al. Autosomal dominant sacral agenesis: Currarino syndrome. J Med Genet 2000; 37:561.
  69. Wender-Ozegowska E, Wróblewska K, Zawiejska A, et al. Threshold values of maternal blood glucose in early diabetic pregnancy--prediction of fetal malformations. Acta Obstet Gynecol Scand 2005; 84:17.
  70. Kang S, Park H, Hong J. Clinical and Radiologic Characteristics of Caudal Regression Syndrome in a 3-Year-Old Boy: Lessons from Overlooked Plain Radiographs. Pediatr Gastroenterol Hepatol Nutr 2021; 24:238.
  71. Twickler D, Budorick N, Pretorius D, et al. Caudal regression versus sirenomelia: sonographic clues. J Ultrasound Med 1993; 12:323.
  72. Valenzano M, Paoletti R, Rossi A, et al. Sirenomelia. Pathological features, antenatal ultrasonographic clues, and a review of current embryogenic theories. Hum Reprod Update 1999; 5:82.
Topic 14405 Version 25.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟