ETIOLOGY Types of NTDs

Anencephaly
Causes
Anencephaly is usually an isolated birth defect and not associated with other malformations or anomalies. The vast majority of isolated anencephaly cases are multifactorial in their inheritance pattern, implicating multiple genes interacting with environmental agents and chance events.

Inadequate folic acid

Adequate folic acid consumption during pregnancy is protective against anencephaly. Exposure to agents that interfere with normal folate metabolism during the critical period of neural tube development (up to 6 weeks after last menstrual period) increases the likelihood of an NTD. Valproic acid, an anticonvulsant, and other antimetabolites of folic acid have been shown to increase the chance of an NTD when exposure occurs in early development. While these induced NTDs are usually spina bifida, the chance of anencephaly is probably increased as well.

IDDM
Maternal type 1, or pregestational insulin-dependent diabetes mellitus (IDDM), confers a significant increase in the risk for NTDs, and it also delays production of alpha-fetoprotein (AFP) during pregnancy. Maternal serum AFP is used as a screening test to detect NTDs, and adjustment of the expected values for AFP in maternal serum must be made if the patient is known to have IDDM. Presumably, well-controlled IDDM confers a lower risk for NTDs, while gestational diabetes does not appear to be associated with any significant increase in NTD risk. The degree of diabetic control is generally monitored using hemoglobin A1c levels.

Maternal hyperthermia
Maternal hyperthermia has been associated with an increased risk for NTD; therefore, pregnant women should avoid hot tubs and other environments that may induce transient hyperthermia. Similarly, maternal fever in early gestation also has been reported as a risk factor for anencephaly and other NTDs.

Genetics
While most NTDs are associated with a multifactorial model of inheritance, rare cases of NTDs are transmitted in an autosomal dominant or autosomal recessive manner in certain families. Such families may have children or fetuses with spina bifida, anencephaly, or other subtypes of NTDs. In families with a pedigree suggestive of autosomal dominant inheritance, reproduction is clearly only possible for the individuals with spina bifida, since death occurs early in the life of individuals with anencephaly. Anencephaly may be associated with the unbalanced form of a structural chromosome abnormality in some families. In these cases, other malformations and birth defects that are not usually found in isolated cases of anencephaly may be present.

Amniotic band disruption sequence

Amniotic band disruption sequence is a condition resulting from rupture of the amniotic membranes. This can cause disruption of normally formed tissues during development, including the structures of the head and brain. Anencephaly caused by amniotic band disruption sequence is frequently distinguishable by the presence of remnants of the amniotic membrane. Recurrence risk for anencephaly caused by this mechanism is lower, and the risk is not modified by the use of folic acid.

http://emedicine.medscape.com/article/1181570-overview#aw2aab6b4

Encephaloceles
Although the exact cause is unknown, encephaloceles are caused by failure of the neural tube to close completely during fetal development. Research has indicated that teratogens (substances known to cause birth defects), trypan blue (a stain used to color dead tissues or cells blue), and arsenic may damage the developing fetus and cause encephaloceles. Proper levels of folic acid have been shown to help prevent such defects when taken before pregnancy, and early in pregnancy. It is recommended that women who may become pregnant take 400 micrograms of folic acid daily.

http://en.wikipedia.org/wiki/Encephalocele

Hydranencephaly
Knowledge about possible etiologies of hydranencephaly comes from various observations and experiments. Studies in sheep and monkeys have demonstrated that bilateral ligation of the carotid arteries results in destruction of the cerebral hemispheres, with relative preservation of the portions of the brain supplied by the posterior circulation, giving an appearance similar to that of hydranencephaly. http://emedicine.medscape.com/article/409520-overview
Hydranencephaly is an extreme form of porencephaly, which is characterized by a cyst or cavity in the cerebral hemispheres. Although the exact cause of hydranencephaly remains undetermined in most cases, the most likely general cause is by vascular insult such as stroke or injury, intrauterine infections, or traumatic disorders after the first trimester of pregnancy. In a number of cases where intrauterine infection was determined the causing factor, most involved toxoplasmosis and viral infections such as enterovirus, adenovirus, parvovirus, cytomegalic, herpes simplex, Epstein-Barr, and syncytial viruses. Another cause factor is determined to be monochorionic twin pregnancies, involving the death of one twin in the second trimester, which in turn causes vascular exchange to the living twin through placental circulation through twin-to-twin transfusion, causing hydranencephaly in the surviving fetus. One medical journal reports hydranencephaly as an autosomal inherited disorder with an unknown mode of transmission, where an unknown blockage of the carotid artery where it enters the cranium causes obstruction and damage to the cerebral cortex. As a recessive genetic condition, both parents must carry the asymptomatic gene and pass it along to their child, a chance of roughly 25 percent. Despite determination of cause, hydranencephaly inflicts both males and females in equal numbers. Though hydranencephaly is typically a congenital disorder, it can occur as a postnatal diagnosis in the aftermath of meningitis, intracerebral infarction, and ischemia (stroke), or other traumatic brain injury.

http://en.wikipedia.org/wiki/Hydranencephaly

Iniencephaly
The etiology for iniencephaly is probably the same as for other NTDs. Seasonal and yearly variations exist. http://books.google.com.ph/books?id=NelULlxsFwC&pg=PA315&lpg=PA315&dq=Iniencephaly+etiology&source=bl&ots=OUw67hq BjI&sig=Nk6MxPzGa_btwRr6dVawlhpThY&hl=tl&sa=X&ei=Tg42T8nkBOyZiQfntcmaAg&ved=0CCYQ6AEwAQ#v=o nepage&q=Iniencephaly%20etiology&f=false No single gene has been identified as the cause for iniencephaly, or any of the neural tube defects. Scientists think these defects have complex causes, mostly likely a mix of genetic and environmental factors. http://patients.aan.com/disorders/index.cfm?event=view&disorder_id=957 The exact cause of iniencephaly is unknown. However, in pregnancies with this and other neural tube birth defects, the mother often has low levels of folic acid before and during the early stages of pregnancy. There is ongoing research to identify whether there are additional factors such as nutrition, environmental, and genetic issues that play a role in this condition. Certain anti-seizure medications may have a role to play in this birth defect happening. http://neuraltubedefect.com/iniencephaly/

Spina Bifida (SPINAL DYSRAPHISM)

Etiology
The etiology in most cases of myelomeningocele is multifactorial, involving genetic, racial, and environmental factors, in which nutrition, particularly folic acid intake, is key. Cytoplasmic factors, polygenic inheritance, chromosomal aberrations, and environmental influences (eg, teratogens) have all been considered as possible causes. A small number of cases are linked to specific etiologic factors. Most infants born with myelomeningocele are born to mothers with no previously affected children. However, other offspring in a family with 1 affected child are at greater risk of neural tube defect than are children without affected siblings. The risk is 1 in 20-30 for subsequent pregnancies, and if 2 children are affected, the risk becomes 1 in 2. An increase in the risk of myelomeningocele has also been reported for second- and third-degree relatives of affected individuals. Up to 10% of fetuses with a neural tube defect detected in early gestation have an associated chromosome abnormality. Associated chromosome abnormalities include trisomies 13 and 18, triploidy, and single-gene mutations. In women with pregestational diabetes, the risk of having a child with a CNS malformation, including myelomeningocele, is 2-10 fold higher than the risk in the general population. The mechanism underlying this teratogenic effect is not well defined but is related to the degree of maternal metabolic control. The risk in women who develop gestational diabetes is lower than the risk of women with pregestational diabetes, but it might not be as low as in the general population. Other risk factors for myelomeningocele include maternal obesity, hyperthermia (as the result of maternal fever or febrile illness or associated with the use of saunas, hot tubs, and tanning beds), and maternal

diarrhea. Intrauterine exposure to antiepileptic drugs, particularly valproate and carbamazepine, and to drugs to induce ovulation are identified risk factors. The risk of having a child with myelomeningocele has also possibly been associated with maternal exposures to fumonisins, electromagnetic fields, hazardous waste sites, disinfection by-products found in drinking water, and pesticides. Research in the 1980s showed correction of folic acid deficiency as an effective means of primary and recurrent prevention. At least half of cases of neural tube defects are related to a nutritional deficiency of folic acid or increased requirement and, thus, are potentially preventable. In September 1992, the US Public Health Service (USPHS) recommended intake of folic acid at a dosage of 0.4 mg/d for all women anticipating pregnancy. In February 1996, the USPHS announced mandatory folic acid fortification of enriched cereal grain, a measure that was expected to increase the daily intake of folic acid in women of reproductive age by approximately 100 mcg/day. After fortification, an estimated 24% decline in myelomeningocele rates was reported to have occurred between 1996 and 2001, based on data from United States surveillance systems. Current fortification programs are preventing about 22,000 cases, or 9% of the estimated folic acid-preventable spina bifida and anencephaly cases.

http://emedicine.medscape.com/article/311113-overview#aw2aab6b2b3 The etiology of spina bifida is unknown but may be multifactorial. Teratogens as well as genetic predisposition probably cause malformations of the neural tube. The former includes hyperthermia, hypoxia, radiation, vascular, infections, trauma, uterine factors, and drugs (Weaver, 1985). Dietary factors such as canned cooked meat, canned peas, white bread, ice cream, tea and blighted potatoes have also been incriminated as teratogens (Carter, 1974). Many studies underscore the importance of multivitamins and folic acid supplements in the prevention of neural tube defects (Smithells et al 1981, Laurence 1982, Mulinare et al 1988, Milunsky et al, 1989, Murphy et al, 2000, Manning et al, 2000). The British Medical Research Council Vitamin Study showed that the daily administration of folic acid before conception and during early pregnancy is effective in decreasing the recurrence of neural tube defects (M.R.C Vitamin Study, Lancet 1991). Most cases of spina bifida are sporadic but a few are familial for which genetic factors may be at play. Chatkupt et al (1992) found that parental sex and genetic imprinting might be significant factors in spina bifida. In their study of 50 families with more than one living case of isolated nonsyndromic spina bifida, gene-carrier females outnumbered gene-carrier males by 2:1. A study in the United States of America found that women who have had a pregnancy complicated by neural tube defect have a 2%-3% risk of having a recurrence (Anonymous MMWR 1991). There is a significant seasonal trend in congenital malformations of the CNS. In Lund, Sweden, spina bifida was preponderant when the last menstrual period was July (Sandahl, 1977). In the United Kingdom, more cases of neural tube defects are born in December- February than in June - August but in Australia, the trend is reversed (Carter, 1974). Chatkupt et al 1994 also observed seasonal variations with more cases born in March and April and fewer cases in January and May. http://book.neurosurgeon.org/? defaultarticle=&defaultnode=2226&layout=22&pagefunction=Load %20Layout&formfields[skip]=1

Spina bifida occulta

At the moment, there is no singular cause which has been linked to this type of neural tube defect. However, there are a few other factors which may make an individual more likely to be diagnosed with this condition. Those who have a parent or sibling with spina bifida are about 8 times more likely to have this disorder as well. Spina bifida occulta has also been linked to a lack of folic acid in the mothers diet. For this reason, healthcare professionals now recommend that all pregnant women take 400 micrograms of folic acid every day in order to help lower their chances of giving birth to a baby with this birth defect. http://spinabifidainfo.com/spina-bifida-occulta/

Meningocele
Causes of meningocele include teratoma and other tumors of the sacrococcyx and of the presacral space, and Currarino syndrome.

http://en.wikipedia.org/wiki/Spina_bifida

Myelomeningocele
Unknown It is thought that agents such as drugs, radiation, malnutrition (Specially folic acid deficiency during prenatal period), and genetics have a role in adversely affecting normal CNS development.

http://www.slideshare.net/imeldamedina/myelomeningocele The cause of NTDs is unknown. The majority are isolated malformations of multifactorial origin. NTDs also occur as part of syndromes, in association with chromosomal disorders, or as a result of an environmental exposure [3-9] . (See Prenatal screening and diagnosis of neural tube defects). http://jneurology.wordpress.com/article/myelomeningocele-1bbsle13m97c0-99/