Vein of Galen malformations
Nov. 28, 2022
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This article includes discussion of anencephaly, anencephalus, cranial dysraphia, cranioschisis, exencephaly, holoacrania, and meroacrania. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Anencephaly is a severe and uniformly lethal malformation, resulting from incomplete closure of the anterior neural tube, in which fetuses or infants present with absent calvarial and cerebral structures. In this article, the author discusses the etiology, pathogenesis, genetic contribution, and epidemiology of anencephaly as well as approaches toward the diagnosis and prevention of this and other neural tube defects.
• Anencephaly represents one of the major forms of neural tube defect, along with encephalocele and spina bifida.
• The prenatal administration of folic acid has proven to be of considerable value in preventing neural tube defects; other vitamins may exert a preventative effect as well.
• A number of women, perhaps as many as 30%, do not benefit from prenatal folic acid, and, for these, the search for risk factors and additional treatment modalities continues.
Anencephaly has probably always existed, although it was not described in recognizable form until the 16th century (16; 97). Numerous classifications and synonyms have led to confusion about the spectrum of anencephaly. Acephalus, acrania, anencephalus, cranioschisis, and cranial or cerebral dysraphia are used commonly but not necessarily correctly. The term "acrania" is, for example, misleading in that it indicates complete absence of the cranium, a condition that is morphologically much more severe than anencephaly. Atelencephaly and aprosencephaly differ from anencephaly in that the cranial vault is covered with skin, cerebral damage probably occurring by means of an encephaloclastic process after closure of the neural tube (169). The degree to which misdiagnosis influences epidemiologic and other studies is unknown.
Anencephaly belongs to a group of congenital malformations known collectively as "neural tube defects" (which also include encephalocele and myelomeningocele). The common neuroanatomical feature in anencephaly is an open defect in the calvaria and skin. The defect varies in size but is often so large that the predominant feature is a degenerated and hemorrhagic mass of tissue lying on an essentially exposed basicranium. One classification that provides a framework for all types of anencephaly is craniorachischisis (head and spine are open), holoacrania (cranial defect extends through the foramen magnum), and meroacrania (partial cranial defect not extending to foramen magnum).
Live born infants with anencephaly generally die quickly, but some may live for days, weeks, or rarely, months. In an exceptional situation, an anencephalic infant, "Baby K," was kept alive on assisted ventilation by order of the Fourth Circuit Court of Appeals, a ruling that caused considerable professional duress (57; 153). To date, the longest survival of an unsupported infant has been 28 months (56). The prenatal ultrasound image published in this case suggested that more brain tissue was present than usual. Surprisingly, affected infants can have seemingly purposeful movements, startle myoclonus, increased tone and deep tendon reflexes, normal cardiovascular status, and regular respiratory patterns. They may experience difficulty maintaining a normal body temperature and become hypothermic. Some infants with anencephaly make crying sounds and are able to swallow. Such lifelike activities create anxiety for caregivers. For these reasons, practitioners are cautioned in the use of language as they counsel families, focusing on the specifics of prognosis rather than abstract generalities (194).
Because of the severity of impairment and frequency of early death, a significant number of workers discuss the option of termination of pregnancy with families (76). Some have suggested that organs of anencephalic infants might be used for transplantation; however, it should be remembered that a significant proportion of these organs are often hypoplastic or malformed (97; 155; 119; 99). A medical task force on anencephaly reviewed the medical, social, legal, and ethical issues regarding anencephaly and recognized a number of complicating factors, including the difficulty in documenting brain death in affected infants (07). In 1995, the ethics council of the American Medical Association announced its support for procuring organs for transplantation from anencephalic infants; subsequent controversy caused the council to withdraw its opinion (193). This issue remains unresolved (141).
Approximately 65% of fetuses with anencephaly die in utero (07). Most liveborn infants with anencephaly die within minutes to hours of delivery, and nearly all die in the first week, though a few long-term survivors have been reported. In a review of 26 patients, the survival time ranged from 10 minutes to eight days (135). Cases carried to term may be complicated by stillbirth, polyhydramnios (sometimes severe), caesarean delivery, shoulder dystocia, and possible obstetrical hemorrhage (59). In twin pregnancies discordant for anencephaly, the risk for premature delivery and low birth weight of the nonaffected twin is elevated, thus, requiring increased monitoring and possible intervention (95; 105). In one small series, an increased risk for neural tube defect was observed among siblings of patients with lipomyelomeningocele (158).
This female infant was born at 39 weeks to a 22-year-old gravida 1 mother who suffered from cervical carcinoma.
The prenatal course was unremarkable, and the mother gave no history of drug or alcohol use or smoking. The infant was delivered by cesarean section for breech presentation and given Apgar scores of 6 at one minute and 9 at five minutes. Moro-like reflexes and grasping could be elicited, but the infant manifested occasional seizure activity and choking. With increasing periodic apnea and bradycardia, she expired at 23 hours.
Anencephaly is etiologically heterogeneous (77; 96). At present, known risk factors account for less than one half of cases (02). A number of etiologic factors have been implicated, but most have not been confirmed or are found only in isolated cases. Implicated factors include maternal exposure to certain drugs (eg, aminopterin, salicylates, clomiphene, and gonadotropins), infections (ie, influenza), nitrite-cured meats, blighted potatoes, and hard water. Difficulties in maternal glucose control, ie, diabetes, hyperinsulinemia, obesity, and intake of simple sugars have been associated with increased risk of neural tube defect and may act by affecting gene expression in the developing embryo (165; 154; 145). Periconceptional maternal cannabis use is associated with the development of anencephaly (186; 150). Maternal hyperthermia, treatment of seizures in pregnant mothers with valproic acid, and the fungal product fumonisin are recognized causes of neural tube defects. One study has identified an association of acute conditions, for example, maternal fever, and more chronic ones, such as migraine headaches, with neural tube defects (118). In one study, the greatest attributable risk for anencephaly was Hispanic ethnicity (02).
A genetic basis for some cases of anencephaly seems likely, but it has been difficult to ascertain because the condition appears to be multigenic (71). A genetic contribution has been suggested by the association with other conditions having a recognized genetic basis, such as anal stenosis, anterior sacral meningocele, and Meckel syndrome (55). A genetic basis is also suggested by the identification of numerous mutations whose function causes neural tube defects in mice (44; 71) and the occurrence of familial cases with 10-fold increase in risk to siblings (29). Familial cases can be striking, with recurrence of three to six affected infants per mother. Demenais and colleagues suggested that familial cases involved monogenic inheritance with environmental influences (52), whereas Kalter and Warkany suggested that a genetic model would most likely involve multigenic inheritance (88; 89). Current thinking supports a multifactorial etiology (44; 71). Analysis of sex ratios show a predominance of female anencephalics, and many twins (usually discordant) have been reported. The increased incidence of anencephaly among twins does not appear to be related to mode of conception (ie, natural vs. artificial) (18). Interestingly, this female predominance is more pronounced in those exhibiting localized cranial lesions than those with schisis involving the upper vertebral column (48). A small percentage of individuals with anencephaly may have an abnormal karyotype. In a study, 2% of fetuses were affected, most often by trisomy 18 or trisomy 13 (159). Two cases of anencephaly associated with partial duplication of 2p have been reported, suggesting that genes on the short arm of chromosome 2 could be important to CNS development (178). A homozygous mutation in FOXN1, a member of the forkhead (or Fox) gene family, has been discovered in a human fetus with absent thymus, abnormal skin, anencephaly, and spina bifida (04). This finding suggests that the gene may be involved in neurulation in humans.
The presence of genetic factors is also supported by the observation that some 30% of defects are not prevented by folic acid supplements alone (22). It is possible that obesity (as quantified by basal metabolic index, or BMI) influences the body distribution of folate (182). The relationship of red blood cell folate levels and obesity appears to vary by BMI, but requires further study (107). Genetic factors presumably confer a risk for developing neural tube defects, but this avenue of research is in its earliest stages and does not yet offer substantive information (15). Important avenues for research include studies of genes controlling folate metabolism (51; 26), screens for human homologs to genes that cause anencephaly in laboratory animals (172), and maternal or sex-influenced genetic effects (49). Mutations in planar cell polarity genes (responsible for maintaining epithelial orientation during neural tube closure) have been identified in mice with neural tube defects and may be functional in humans as well (50; 87). The regulatory effects of bone morphogenetic protein and Sonic hedgehog have been implicated in neural tube bending and may play a role in pathogenesis (45), as may maladjustment of microRNAs in the mitogen-activated protein kinase signaling pathway (204).
The pathogenesis of anencephaly remains unclear. Two major schools exist; one holding that the primary mechanism is nonclosure of the rostral neural folds, and the other that cranial mesenchyme is defective primarily (109; 125). Most workers favor nonclosure of the neural tube as the primary mechanism, as evidenced by the widespread popularity of the term "neural tube defect" to designate anencephaly, encephalocele, and myelomeningocele. A third possibility is that a closed neural tube reopens, but supporting evidence is weakest in this area.
In human embryos, primary neurulation (closure of the neural folds) takes place between stage 8 and stage 12 (see Table 1). Anencephaly and other neural tube defects occur when development is abnormal, although the exact mechanism of closure remains unknown. The Hedgehog signaling pathway has been implicated in neural tube closure, for increased Sonic Hedgehog signaling is associated with the appearance of exencephaly (126). Embryonic metabolism appears to be important, as studies using mass spectrometry have identified abnormalities in glucose metabolism during neural tube closure (199).
Some investigators have postulated that the variations of anencephaly and other neural tube defects can be explained by multiple sites of closure of the neural tube (185; 70; 171). Others counter that “accessory loci” for closure exist in human embryos but are highly variable and do not follow a constant pattern (138). To a large extent, knowledge is fortuitous and depends on the study of affected embryos, which are rare and appear to die at very early ages (ie, 5 to 6.5 weeks) (127). Two anencephalic embryos, stages 13 and 22, are exceptions to this, having intact neural crest derivatives (139). The observation suggests that the process responsible for anencephaly began after the initiation of crest cell migration or that crest cells survived the pathogenetic event.
Results of maldevelopment
Neural folds appear
Brain and spinal cord exposed and dysplastic (ie, early craniorachischisis)
First fusion of neural folds
Closure of rostral neuropore optic vesicle
Closure of caudal neuropore; primary neurulation ends in this stage or stage 13
Myelomeningocele; myelocele; encephalocele
* Postovulatory days are approximate (137; 125; 100).
An understanding of these stages is important in research and for counseling parents. Anencephaly can be said to have a "termination period" (ie, a time after which the anomaly cannot occur); therefore, exposures or other maternal events that occur after the critical periods for anencephaly can be ruled out as causative factors.
Exencephaly, the superior extrusion of a relatively large, bulbous portion of cerebral tissue beyond the calvaria, is a forerunner of anencephaly (198; 125). This has been demonstrated experimentally and by prenatal ultrasonography in fetuses prior to spontaneous degeneration of brain tissue. Holoprosencephaly is rarely associated with anencephaly (98; 167) and may involve aberrant morphogenesis of prechordal and paraxial developmental fields (168). The genetics of neural tube defects and midline craniofacial malformations is becoming understood, as illustrated by studies of the tuft mouse mutant (67).
Pathological findings in the central nervous system depend on the gestational age and extent of the lesion. Rudimentary cerebral hemispheres can be found in 50% of anencephalic newborns, and complete absence can be found in the remainder. Absence of the cerebellum and brainstem has also been reported (187). These infants usually manifest a connective tissue mass adherent to the dura mater. Their cerebral tissue is soft and infiltrated with blood, and scattered islands of neural cells and choroid plexus can often be identified. As a result of this appearance, the term "area cerebrovasculosa" is often applied to the anencephalic brain. This vascular finding is a reactive change to the exposure of neural tissue to amniotic fluid.
Examination of the brainstem reveals variability in the preservation of nuclei and absence of the pyramidal tract. The eyes often bulge dramatically. They may also appear normal but lack central connections to the brain, ending blindly posterior to the optic foramina. Other pathological changes of the eyes include absence or reduction in axis cylinders and colobomata of the optic disc. The spinal cord may show reduced white matter in some tracts, absence of Clarke column, and a lower termination of the conus medullaris.
Cranial bones are also highly abnormal (64; 125): calvarial bones are displaced, rudimentary, or absent; the zygomatic bones may be rotated abnormally; the sphenoid is hypoplastic in the cranial base; and petrous ridges are malpositioned. The maxillae, palatine bones, and vomer may be normal, although the mandible is large and prognathic. Temporal and occipital bones may also be malformed (14). An understanding of this bony anatomy has proven especially helpful in certain forensic situations (58).
Many other interesting associations or pathological findings occur in anencephaly. Not all are clearly related to the mechanism(s) responsible for the development of anencephaly. One study found that liveborn anencephalics had 12.3% additional malformations of other systems, but if there was an associated spina bifida or encephalocele, the prevalence was 87.7% (155). Anomalies of extraocular muscles have been observed in a large percentage of affected fetuses (143). Endocrine system anomalies are present in anencephalic infants with absence or hypoplasia of the pituitary gland, and the adrenal glands are hypoplastic in nearly all cases (114). Diaphragmatic malformations (eg, hernia or eventration), abdominal wall defects, and other thoracic cage abnormalities are common (97; 119). Frequently, the lungs and heart are hypoplastic. One study has demonstrated various degrees of intestinal aganglionosis in anencephaly (112). Anthropometric studies have shown an increased growth of the arms in anencephaly (128). A proximodistal gradient existed with the upper arm being increased by 24%, the forearm by 16%, and the hand by 2%. This is a variable finding, for Barr has observed normal arm length in anencephaly (Barr, personal communication 1997). Other anomalies of the limbs are found, but no one abnormality stands out, except perhaps talipes equinovarus. One detailed anatomic study identified several anomalies of skeletal muscles in a single fetus (03). A sternalis muscle is present in up to 50% of anencephalics but is unusual in the general population (1% to 4%).
Anencephaly is often discussed within the framework of other neural tube defects, including myelomeningocele. Epidemiological studies sometimes combine these entities, which is a point that should be remembered if one is interested specifically in anencephaly. One needs also to ensure that the diagnosis of anencephaly is a correct one, ruling out other equally devastating but etiologically and pathogenetically distinct conditions such as atelencephaly, aprosencephaly, and craniocerebral damage due to amniotic bands.
Only congenital cardiac defects are more common than neural tube defects. Over the past 50 years, the prevalence of anencephaly has averaged about 1 per 1000 deliveries, but wide variations exist geographically and by race (43). The worldwide prevalence is estimated to be at least 300,000 cases per year (111). The highest rates reported were in China (14 per 1000), Ireland (4.6 to 6.7 per 1000), South Wales (3.55), Liverpool (3.15), Scotland (2.59), Egypt (3.75), and Lebanon (3.05). The prevalence was low in Colombia (0.1 per 1000), Norway (0.2), France (0.5), Hungary (0.5), New York (0.5), Yugoslavia (0.6), and Japan (0.6). Average rates of 1 per 1000 have been reported in Copenhagen, Holland, Russia, Malaysia, Madras, Kenya, and Taiwan. These figures do not take into account the large number of anencephalic embryos and fetuses that undergo spontaneous abortions and may or may not include therapeutic terminations (24; 60; 101; 142). In fact, reports of the declining prevalence of neural tube defects may be influenced significantly by pregnancy termination (177). An estimated 83% of pregnancies complicated by anencephaly and 63% of cases with spina bifida undergo termination (83). The termination rate in France is estimated at 97% (181). Data from these cases may not be available in the form of death certificates or other formal documentation.
These points are borne out by a study in Japan, wherein an extensive review of over 311,000 deliveries and terminations in cases of myelomeningocele and anencephaly disclosed a prevalence of 8.29 to 8.72 per 10,000 deliveries (2014 and 2015 data) (93). Pregnancies involving anencephaly were terminated in 80%, an indication of the potential magnitude of data that may be lost if only live births are reported. Rates may also fluctuate over time and among different cultures. British Columbia, for example, has experienced a decline in the occurrence of neural tube defects (but also an increase in the severity of lesions) and a striking decrease in recurrence from 2.3% to 0.24% (39). The birth prevalence in Ireland (where terminations are illegal) has dropped 4-fold from 1980 (46.9 per 10,000 births) to 1994 (11.6 per 10,000 births) (116). This resembles the current prevalence for Germany (12.36 per 10,000 births), a country that lags in folate fortification at present (75). By contrast, a decrease in birth prevalence in northern England is attributed to improved prenatal diagnosis and intervention (147). An increased prevalence of anencephaly has been noted among Hispanics in south Texas. Hispanics have a prevalence three times higher than non-Hispanics (30), though no difference exists between Hispanics born in Mexico and Hispanics born in Texas (31). This difference in prevalence has also been noted in California, where Hispanic women were 45% more likely to have an anencephalic conceptus than white women (63) and elsewhere in the United States (23). In a cluster of neural tube defects, mostly anencephaly, in central Washington state, the rate was four times the national average (37). In this study, no significant differences were found between cases and controls. The area is largely rural, and so an effect of pesticides and other agricultural materials might be postulated. However, an epidemiological study from California did not identify an association between pesticide exposure and neural tube defects (200).
The search continues for epidemiologic factors related to anencephaly, though disagreement regarding methodology persists (21). Perhaps most exciting is the success of increased dietary folates in preventing neural tube defects. This finding appears to confirm the longstanding view that nutritional deficiencies play an important role in causation. The prevalence of anencephaly has increased during periods of poor maternal nutrition (for example, the Great Depression and wartime famines), and it has dropped with global socioeconomic development (123). Folic acid supplementation is successful in reducing the prevalence of defects in Hispanic and non-Hispanic white patients, but not necessarily blacks (09; 173; 68; 195). The fortification of corn masa flour, a food used in Hispanic food preparation, could be useful in further reducing neural tube defects in Hispanics (72; 124). Continuing studies suggest that other risk factors, including low serum B12, high serum homocysteine, diarrhea, stress, fumonisins, high nitrate or nitrite intake, and obesity, play a role in Hispanics living on the Texas-Mexico border as well (175).
Other environmental influences have undergone intense scrutiny. As a result of the increase in neural tube defects associated with influenza epidemics, infectious agents have been targeted. The effects of aminopterin and salicylates have been discarded. The former substance has been withdrawn, and the latter proved negative in several studies. Blighted potatoes, hardness of water, intergenerational influences, religion, parity, migration and ethnic factors, and seasonal and secular variations have provided no common denominator. Low maternal age has been observed in a Russian/Norwegian study (142); low maternal age has also been associated with spina bifida in a broader meta-analysis (188). In the latter study, advanced maternal age (greater than 40) was also associated with an increased risk for spina bifida, and to a lesser extent, anencephaly. The increased prevalence of anencephaly among some impoverished groups raises several issues, especially nutrition, as factors. Foods that are rich in folate may lower the risk of neural tube defects, whereas conversely, foods that interfere with folate metabolism may result in increased risk (102; 33). Although certain foodstuffs have been implicated, final proof may be difficult, especially in instances where a particular dietary substance is used widely. For example, one group of researchers has proposed that daily tea drinking is a risk factor for neural tube defects (202). Given the widespread use of tea in China, one might be tempted to discount the proposition, except that certain substances in tea (catechins) have been shown to interfere with the folate metabolic pathway. More research may help to clarify this.
Efforts should be directed toward the study of occupational and environmental exposures, particularly organic solvents, pesticides and other chemicals used in agriculture, water nitrates, heavy metals (eg, mercury), ionizing radiation, the byproducts of water purification, and hazardous waste (161; 140; 94; 152). One paper, for example, suggests that paternal exposure to organic solvents is associated with increased risk for neural tube defects (103). Another has found a positive association between maternal exposure to chlorinated solvents in early pregnancy and neural tube defects (53). Paternal age does not appear to be a factor (13). Maternal stress, arising from challenging life events, has been associated with a 2.35-fold increase in risk for women who did not take folate supplements and a 1.42-fold increase in women who did (32). Overarching reviews of the epidemiology of neural tube defects suggest that a host of interactions, including gene-gene and gene-environment, as well as maternal genetic effects, probably affect the risk of neural tube defect (121; 151).
Many epidemiologists make use of data contained in death certificates, but this approach can be problematic. Death certificates may be imprecise or inaccurate (164). The diagnosis of anencephaly in death certificates relies on the expertise and experience of the individual completing the document. Fetuses dying by natural means or pregnancy termination before 20 weeks elicit no death certificate and are excluded from bureaucratic scrutiny. By one estimate, over one third of anencephalic fetuses may not be included in published frequencies, which, for this reason, are low (192).
Although the prevalence of anencephaly averages about 1 in 2000 live births, the recurrence risk is 100 times higher (about 1 in 20). Recurrence is higher for syndromic forms than isolated ones (41; 42). Many preventative efforts, therefore, have been directed toward pregnant women who have had a previous child with anencephaly or other neural tube defects. Although these ventures have helped reduce the prevalence of anencephaly at birth, they do not address total prevention of the problem.
Some approaches have involved the use of folates (ie, folic acid or a B vitamin) to prevent neural tube defects. The results of several trials worldwide have demonstrated the effect of folic acid supplementation before and during early pregnancy in reducing the prevalence of first-time neural tube defects by as much as 70%. Fortification of foodstuffs alone is insufficient in many cases; its effects can, for example, be impacted adversely by dieting (11). In fact, a 2018 study demonstrated an association between low carbohydrate diet and anencephaly or spina bifida (54). In that study, women with a carbohydrate-restricted diet were 30% more likely to have a baby with one of these defects. In a follow-up study, workers confirmed this association, indicating that the increased risk was not due to low folic acid intake (166). This finding may have application to the issue of folate-insensitive neural tube defects.
Efforts are underway to monitor the use and efficacy of natural and exogenous forms of folic acid, with the goal of making both available worldwide (133; 134). One study has shown a decrease in cases of neural tube defects in the United States from 4000 per year (1995-1996) to 3000 (1999-2000) following fortification of foods with folic acid (35). A decrease of 31% has been noted in Chile (34); a notable decrease has also been observed in Brazil following mandatory supplementation of flour (156). Folic acid is also successful in preventing recurrent neural tube defects (190; 148; 173). At present, it is recommended that all women contemplating pregnancy supplement their diet with 0.4 mg folic acid daily (191; 08; 66). In a study conducted in the United States, women at highest risk were young, unmarried, obese smokers who ate few fruits and vegetables and had a low level of education (10). In the Texas-Mexico border region, an area recognized for an elevated incidence of neural tube defects, women living in poverty are at increased risk for having a baby with craniorachischisis (84). Supporting an economic influence is the observation that women employed in industry or agriculture have a higher risk (6.5 times) of having an anencephalic baby than business or professional women (20). But even when the effects of maternal age, education, ethnicity, tobacco and alcohol use, and vitamin use are removed statistically, obesity and gestational diabetes remain risk factors (05). A recent study identified no association between maternal alcohol consumption and anencephaly (104). A lack of periconceptional folic acid appears to be associated with an increased risk for birth defects in women with diabetes mellitus (47). Women who have a neural tube defect or a child with a neural tube defect should take 5 mg of folic acid daily (148). The use of both supplemental vitamins and fortified foods (ie, cereals) could contribute significantly to the reduction in neural tube defects (130; 131; 27; 78) and, indeed, several studies point in that direction (61; Martinez et al 2002; 113; 197). Present estimates suggest that between 15% and 25% of folic acid-preventable neural tube defects are being prevented globally (203). Additional micronutrients, including thiamin, riboflavin, betaine, vitamins A, B6, C, and E, niacin, iron, and retinol may also decrease the risk of neural tube defects (40). The need for fortification is ongoing, as women seem to be inconsistent in taking folic acid supplements during their childbearing years (36; 92), and making recommendations alone appears to be insufficient for prevention (174). Governing bodies are sometimes slow to develop policies as well (132). Women aged 18 to 24 years seem to be least aware of the need for supplementation (12). This appears to be the case for women of all educational levels, and so attempts to inform this age group of the importance of folic acid continue (146). One survey has shown that physicians do not always understand the timing or dosage of folate administration (01). Women who have undergone gastric bypass are at special risk, perhaps because obesity is a risk factor but also because folates and other vitamins are absorbed less completely following this procedure (122). Clearly, ongoing surveillance is necessary (17). Harmful effects of folic acid supplementation have not been identified (189).
All of this is not to suggest that the issue of folate supplementation is settled. In at least one study, the prevalence of anencephaly remained constant before and after folic acid use was instituted (181). Beyond this, the physiologic effects of folic acid are complex and incompletely understood. For example, an association between deficiencies in folate level and increased pregnancy loss has been suggested (149), but agreement on this issue is not universal (176). The contrary view, that folic acid supplementation reduces the prevalence of neural tube defects by inducing miscarriage in affected fetuses, has also been put forth (79; 80; 79). The view has been refuted (149; 19). It is also possible that exposure to folic acid antagonists (ie, carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) increases the risk for neural tube defects (74). In fact, women taking antiepileptic drugs are at increased risk for having a baby with neural tube defect (65). Folic acid supplementation does not appear to reduce the risk of neural tube defect in women taking these drugs (68). Some of this confusion may stem from the fact that folate resistance appears to occur in some humans, perhaps up to 30% of cases. Resistance has also been observed in certain mouse models, some of which have been treated successfully with inositol. It is possible that this drug will come to be used in humans as well (46; 183). It has been suggested that excess homocysteine may play an independent role in the development of neural tube defects and that elevated blood levels could be predictive of risk (62; 175).
Most infants with anencephaly are easily diagnosed. Whenever cerebral remnants are visible through a defect in calvaria and skin, the diagnosis can be made; however, confusion may still result because infants with extreme microcephaly (ie, atelencephaly or aprosencephaly), microcephaly with an encephalocele covered by thin, nearly transparent fetal skin, or defects resulting from amniotic bands can be mistakenly diagnosed as anencephalic (86).
Prenatal diagnosis is primarily accomplished by imaging and the finding of an elevated alpha-fetoprotein through screening. When used alone, imaging appears to be more successful in diagnosing neural tube defects than screening (129). Substantive differences in screening policies still exist worldwide (25). Although these two tests have been generally successful, a significant number of cases are still missed (196). First trimester ultrasonographic diagnosis is possible at routine nuchal translucency examination, as early as eight to 10 weeks, permitting further workup or termination of pregnancy when desired (85; 106; 90). Three-dimensional ultrasonography may confirm or further elucidate diagnoses made by 2-dimensional techniques (73). Fetal magnetic resonance imaging has also been used with success (162; 28), and may be especially helpful in cases where prenatal ultrasound diagnosis is inconclusive (163). In general, amniotic fluid alpha-fetoprotein is reliable at and after 14 weeks. Maternal serum alpha-fetoprotein is most reliable at 16 weeks to 18 weeks. Elevations in maternal serum alpha-fetoprotein occur at the fetal-maternal interface and, therefore, amniotic fluid alpha-fetoprotein is not uniformly elevated in anencephaly. The finding must be evaluated carefully and supplemented with imaging studies, as other factors also result in elevated maternal serum alpha-fetoprotein (eg, gestational age, number of fetuses, maternal weight, race, presence of diabetic condition, or placental abnormality) (180). The combination of elevated maternal serum alpha-fetoprotein and low estriol appears to be especially predictive of anencephaly (201). Some workers are beginning to examine the use of these tests from an economic point of view (170). The search for additional biomarkers continues (184).
The postnatal diagnosis of anencephaly is made by physical examination. No tests are necessary, although radiography may help elucidate cranial anomalies as well as other unexpected changes. For example, a case of anencephaly with sirenomelia and renal agenesis was diagnosed by prenatal ultrasound, confirmed by postnatal radiography, and diagnosed as axial mesodermal dysplasia syndrome (179). The value of autopsy in identifying anomalies not discernible by imaging should not be overlooked (38; 91).
Neural tube defects will be encountered by practitioners, especially those in a pediatric setting. In a review of CNS anomalies diagnosed prenatally, nearly one half were neural tube defects (108). Management is limited, as most liveborn anencephalics die soon after birth. The median survival time was 55 minutes in one study, although survival of 10 weeks has been reported (144). Comfort care for the affected infant, and parental, and even staff, counseling are necessary (135). The ethics of transplanting organs from anencephalic infants has been debated for many years and continues (07; 115; 141; 120). Families should be counseled regarding this possibility (82), or the opportunity to donate tissue for research. Practitioners should be aware that formal procedures have been established for this purpose (157; 06). Treatment of patients with other neural tube defects is, of course, highly diverse (69). Regardless of the nature of the defect, careful perinatal counseling is indicated (136).
Pregnancy in mothers carrying anencephalic fetuses is complicated by polyhydramnios, shoulder dystocia, and an increased fetal death rate (135). In cases of discordant monoamniotic twin pregnancy, the anencephalic twin may pose a risk to the survival of the healthy co-twin. In such cases, selective termination has been performed (160). Parents will be expected to sustain considerable grief over the loss of one twin, and benefit from compassionate perinatal palliative care (117).
Anencephaly is a lethal disorder, and affected individuals are highly unlikely to undergo procedures that would require anesthesia.
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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