R E V I E W A R T I C L E
Oral Biosciences
Neural tube defects and their significance in clinical dentistry: a mini review
Anuradha Garg1, Ashok Utreja1, Satinder P. Singh1& Suresh K. Angurana2
1 Unit of Orthodontics, Oral Health Sciences Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India 2 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Keywords
anencephaly, encephalocele, myelomeningocele, neural tube defect, spina bifida.
Correspondence
Dr Anuradha Garg, Department of Orthodontics and Dentofacial Orthopedics, School of Dental Sciences, Sharda University, Plot no. 32, 34, Knowledge Park III, Greater Noida, Uttar Pradesh 201306, India.
Tel: +91-96549-88887
Email: garg.anuradha@yahoo.co.in
Received 9 February 2012; accepted 7 April 2012.
doi: 10.1111/j.2041-1626.2012.00141.x
Abstract
Neural tube defects are common congenital malformations that could be apparent at birth or manifested in later stages of life. Morbidity is high in anen- cephaly, whereas in spina bifida, there are neurological and motor disorders.
These defects deserve paramount importance in clinical dentistry. Latex allergy, dental caries, difficulty in mouth opening, and sitting in a dental chair are com- mon problems. There is a high risk of anaphylactic response during anaesthesia.
There could be associated craniosynostosis causing maxillary deficiency, and malformed sella turcica might be seen. An association of the defects has been linked with orofacial clefts and Down syndrome.
Introduction
Neural tube defects (NTD) are malformations secondary to abnormal neural tube closure. They manifest between the third and fourth weeks of gestational age, resulting in structural defects that occur anywhere along the neural axis from the developing brain to the sacrum.1
Methodology
A literature search using the Medline database, PubMed, and Google was conducted for articles published between 1975 and 2011. Searches of systematic reviews using the Cochrane database and websites of international dental organizations were also conducted.
Etiology and pathogenesis
Genes interact with environmental factors and play a joint role in the causation of NTD.2 Genes, such as Sonic Hedgehog,3 the dishevelled and thermolabile variant of
methylenetetrahydrofolate reductase (MTHFR), have been held to be responsible for NTD occurrence.4,5Infants with mutations in the folate receptor-a gene are at increased risk of NTD due to reduced binding affinity to 5-MTHF, which is the physiological form of folic acid. NTD can also result from hyperhomocysteinemia that arises as a result of deficiency of vitamins B6, B11and B12, which are involved in the methylation cycle.6 Low socioeconomic status, smoking, excess vitamin A, zinc deficiency, and high levels of organic matter have been cited as the risk factors for NTD occurrence. Maternal obesity, diabetes, the common cold in the first trimester, hyperthyroidism, stress, hyperthermia, and infections have been found to be associated with NTD.7 The use of antiepileptic drugs during pregnancy is associated with an increased risk of NTD, due to free-radical induced damage.8
Theories of neural tube closure
Neural tube defects can be classified by closure sites where failure of closure occurs.5
Five sites of initiation of neural fold fusion
Consistent with the Van Allen model, closure 1 occurs at the rhombencephalon–spinal cord junction and extends rostrally and caudally. Closure 2 starts at prosencephalon–
mesencephalon junction and progresses bidirectionally.
Closure 3 begins at the rostral tip of the neural plate adjacent to the stomodeum, and progresses caudally to meet closure 2. Closure 4 starts between closures 1 and 2 over the rhombencephalon, and completes closure of the cranial portion of the neural tube from which the brain develops. Closure 5 starts at the caudal end of the neural groove and extends cranially to meet closure 1, completing closure of the spinal portion of the neural tube.
Three sites of initiation of neural fold fusion
Sites 1 and 3 are similar to the Van Allen model. Site 2 varies in position along the rostrocaudal axis.
Two sites of initiation of neural fold fusion
Sitea is in the region of the rhombencephalon, and site b is in region of the rostral tip of the prosencephalon.
Classification of NTD
Neural tube defects have been classified into open and closed types, based on embryological considerations and the presence or absence of exposed neural tissue.9 Open NTD are the most common type, and occur due to failure of primary neurulation. They occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae with associated cerebrospinal fluid leakage (e.g. spina bifida, anencephaly, and encephalocele).
Closed NTD result from a defect in secondary neurulation, and are confined to the spine. Neural tissue is not exposed, and the defect is fully epithelialized (e.g. lipomyelomen- ingocele and tethered cord). Based on gross anatomic findings, these have been categorized into defects affecting cranial structures, such as anencephaly and encephalocele, and those involving spinal structures, such as spina bifida.1
Epidemiology
The incidence of NTD is 6.57–8.21 per 1000 live births in the Balrampur district of Uttar Pradesh, India, a region ranked as the least developed in the subcontinent.10 The incidence of NTD in this region is among the highest worldwide. In the USA, the incidence of NTD declined by 50% between 1970 (1.3/1000 live births) and 1989 (0.6/
1000 live births). In the UK and Ireland, the annual preva- lence of NTD declined from 4.5 per 1000 live births in
1980 to 1.0–1.5 per 1000 live births in the 1990s.11 In northern China, there was a 79% reduction NTD after the addition of folic acid supplements to women’s diets (6.5/
1000–1.3/1000 pregnancies).12In Australia, the prevalence of NTD (births + termination of pregnancies) was two per 1000 births for the period 1990–1994, but decreased to 1.2 per 1000 births in 2009. In 2009, very few infants (0.3/1000) were liveborn with a NTD.13Anencephaly has a female predominance, with a female-to-male ratio of 3:1.
Risk tends to be higher in older or very young mothers.
After the first NTD-affected pregnancy, the risk of a subse- quent NTD-affected pregnancy is almost tripled. However, 95% of the affected infants are born to parents with no family history of NTD.1,14
Clinical presentation
Anencephaly, encephalocele, and craniorachischisis totalis are cranial presentations. Spinal presentations include spina bifida, myelomeningocele, congenital dermal sinus, lipomatous malformations, split-cord malformations, and caudal agenesis. Anencephaly is a serious developmental defect of the central nervous system in which the cere- brum, cerebellum, and cranial vault are either reduced in size or absent. It is classified anatomically as meroacrania if the defect does not involve foramen magnum, as holo- acrania if it extends through the foramen magnum, and as holoacrania with rachischisis if anencephaly is accom- panied by spina bifida. The majority of anencephalic fetuses are stillborn or aborted spontaneously.15
Spina bifida is a birth defect affecting the spinal column.
Spina bifida occulta, meningocele, and spina bifida cystica (myelomeningocele) are the three types of spina bifida (Figure 1). Patients with spina bifida can have disabling conditions, such as cognitive deficit, pulmonary function abnormalities; scoliosis; hip, foot, and leg deformities;
bladder dysfunction; and short stature. Myelomeningocele patients have a 90% chance of having hydrocephalus, which causes cognitive deficits.16,17
Figure 1. Lumbar myelomeningocele.
Cephalocele is the herniation of the brain or meninges through a defect in the skull. It has been classified as occipital, parietal, or anterior. Associated abnormalities include hydrocephalus, spastic quadriplegia, microcephaly, vision problems, mental and growth retardation, and seizures.
Significance in clinical dentistry Anencephaly
Craniofacial malformations include hypoplastic or low-set ears or both; ocular proptosis; microphthalmia; subcuta- neous nasal cleft; absent or incompletely-defined phil- trum, cleft lip, cleft palate, bifid uvula, microstomia; and prominent maxillary alveolar ridges. Cephalometrically, the mandible is prognathic in every case. The thyroid gland might be normal, small, or larger in size. The neu- rohypophysis is hypoplastic and frequently found in the craniopharyngeal canal, which usually remains open in anencephaly. The hypothalamus is absent. The anterior and middle cranial fossae are constricted laterally, and the posterior cranial fossa is increased in lateral extension, but constricted anteroposteriorly.15 The lesser wings of the sphenoid bone are rudimentary and extend parallel to the midline. The squamae of the frontal bone are reduced in size and form most of the orbital roofs. The posterior height of the vomer is increased, and the nasopharynx is enlarged. Zygomatic bones are rhomboid shaped in lateral view. The cranial base angle is reduced to a mean of 112.6 16.9, with a more vertically-oriented clivus.18
Spina bifida
Hydrocephalus is a common residual problem in patients with myelomeningocele and is usually treated by shunt placement (Figure 2). Penicillin is commonly prescribed for shunt prophylaxis to prevent infective endocarditis in patients undergoing invasive dental pro- cedures. Extractions and scaling/root planing are per- ceived to be high-risk procedures in patients with spina bifida.19 The child is unable to open his mouth for a prolonged duration. Adaptive dental aids, such as a bite block, tongue retractor, and rubber dam, need to be used to control tongue movements and prevent swal- lowing of foreign materials.
The patient usually encounters difficulty sitting in the dental chair. Body position needs to be changed fre- quently to avoid pressure sores and uneasiness. Most patients with spina bifida have lower limb deformities and might need to be treated in their wheelchair, or an assistant might be needed to help the child move to the dental chair.20
Patients with spina bifida usually have pulmonary function abnormalities and apnoeic episodes as a result of brain stem dysfunction due to Chiari malforma- tion.21 Thorough preoperative preparation should be done to decrease the risk of anaphylaxis during anaes- thesia.
Children with these defects are more prone to child- hood dental caries, because their neurological impairment can make dental care difficult, resulting in poor oral hygiene. These children also have poor nutrition, have to take medications containing sugar, and due to their phys- ical problems, less attention is paid to their oral health.
Therefore, these patients require periodic dental check- ups and proper dental care.22
Children with spina bifida have a latex allergy preva- lence of 28–67%. Thus, proper latex precautions should be taken in all patients during dental appointments. Den- tal products containing latex include gloves, rubber dams, mouth props, orthodontic elastics, toothbrush handles, polishing points, suction tips, and impression materials.23
Craniosynostosis in NTD
Patients with NTD can have diminished intrauterine movements, which in turn could help maintain the head in a fixed position against the pelvic bones. Facial bones are fused, resulting in a flat mid-face and protruding eyes.
The patient exhibits a contracted upper jaw, resulting in a cross-bite and severely crowded teeth. Orthodontics and
Figure 2. Non-contrast computed tomography image of head with dilated lateral and third ventricles, suggestive of obstructive hydro- cephalus.
mid-face advancement might be done early in life or after growth completion, depending on the particular needs of the child.24
Sella turcica in myelomeningocele
The anterior wall of the sella is found to be obliquely ori- ented in an antero-posterior direction instead of following a normal cranio-caudal direction, giving an impression of a wide sella turcica with less depth than normal (Fig- ure 3). Because orthodontists regularly analyze a consid- erable number of lateral cephalograms, they will in many cases be the first to know the minor malformations of sella turcica. Appraisal of the morphology of sella turcica can be valuable in assessing any pathology in the pituitary gland.25,26
NTD and orofacial clefting
Neural tube defects and cleft lip, alveolus, and palate (CLAP) are the most common malformations in humans.
NTD occurs at a rate of 1:1000, and CLAP between 1:500 and 1:1500. Both NTD and CLAP are known to be caused by a deficiency of folic acid and vitamin B6 during preg-
nancy, but do not occur in combination. Both occur dur- ing the embryonal period, and are based on the closure failure of respective structures. The combination of the two malformations is virtually never observed clinically, except in genetic syndromes, such as anophthalmia clefting NTD and Wildervanck syndrome.27
NTD and Down syndrome
All or at least some cases of NTD and Down syndrome could have a common etiological pathway associated with impaired maternal folate metabolism. Mothers of infants affected with NTD have an increased frequency of muta- tions in the genes encoding MTHFR, although not neces- sarily for Down syndrome. The two have common epidemiological features, such as a large maternal contri- bution to both risk of occurrence and recurrence, increased number of miscarriages, ethnic differences, and maternal age. Although the underlying mechanism for the connection between the disorders needs to be established, direct evidence of the link between the two implies that folate supplementation before conception can reduce the frequency of Down syndrome.28
Diagnosis
Obtaining the patient’s history and conducting a physical examination and screening are essential. Differential diag- nosis includes neonatal meningitis; spinal cord hemorrhage and infarction; spinal epidural abscess; staphylococcal, tuberculous, and viral meningitis; and cervical and lumbo- sacral disk syndromes.
Prevention and treatment Primary prevention: folic acid
In high-risk women, folic acid supplementation of 4 mg/day 3 months before conception and during the first trimester is recommended.29
Secondary prevention: screening
Maternal seruma-fetoprotein (MSAFP) test is performed on a pregnant woman’s blood at approximately 16–18 weeks of pregnancy. High-resolution ultrasound detects NTD after approximately 18 weeks of pregnancy. Amniocentesis sam- ples the amniotic fluid after 15 weeks of pregnancy. If MSAFP levels are elevated, ultrasonography is undertaken to rule out other possible explanations, such as multiple gesta- tions, diabetes mellitus, and fetal malformations. If ultraso- nography provides no explanation, amniocentesis is usually performed.30
(a)
(b)
Figure 3. Lateral radiograph of sella turcica (a) and normal morphol- ogy (b). Abnormal morphology with diverging anterior and posterior walls in a patient with myelomeningocele.
Treatment
Proper medical and surgical care should be rendered by the neonatologist, neurosurgeon, orthopedician, and urologist. Newborns with an open NTD should be kept warm, and the defect covered with a sterile saline dress- ing. Prompt closure of the defect should be done. The patient should be positioned in a prone position to pre- vent pressure on the defect.
Conclusion
NTD are of immense importance to the dental profession.
The chances of increased caries, plaque, latex allergy,
physical impairment, and anesthesia problems in spina bifida patients need to be considered. Alteration of the cranial base angle and prognathic mandible and sella tur- cica morphology can be predicted from cephalograms.
Oral and maxillofacial surgeons and orthodontists have an important role in assessing craniofacial malformations and facial skeleton morphology, and treating craniosynos- tosis cases with appropriate surgeries. The association between NTD and conditions, such as cleft and Down syndrome, in some studies cannot be ignored.27,28 There- fore, dentists need to be well educated about these mal- formations, their etiology, screening, preventive measures, and relevance to the profession.
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