Myelomeningocele in an infant with intrauterine exposure to efavirenz.

We report a case of myelomeningocele in an infant whose mother was exposed to efavirenz during the first 16 weeks of pregnancy. Although the true risk for myelomeningocele with the use of efavirenz early in pregnancy is still unknown, the findings in humans are consistent with those observed in primates and suggest that efavirenz is a potent teratogen. Thus, we suggest that efavirenz only be prescribed for women of childbearing potential when no other comparable antiretroviral options are available.

Morphogenesis of experimentally induced Arnold--Chiari malformation.

The administration of a single dose of vitamin A to pregnant hamsters, early during the morning of their 8th day of gestation, induces types I and II Arnold--Chiari malformation (ACM), as well as various types of axial skeletal-dysraphic disorders known to be associated with the human disease. This new model provides a means of carrying comparative studies between the axial skeletal defects and neurological anomalies of this complex developmental malformation with those which characterize the other induced disorders related to it. Study of this experimental model has demonstrated that the basichondrocranium of fetuses with ACM is shorter than normal and slightly elevated (lordotic) in relation to the axis of the vertebral column. The shortness of the basichondrocranium of these fetuses is caused by the underdevelopment of the occipital bone specially noticeable in its basal component (basioccipital). This basic defect has resulted in a short and small posterior cerebral fossa which is inadequate to contain the developing nervous structures of that region. The developing cerebellum is displaced downward to an anomalous position just above the foramen magnum; and, the developing medulla is compressed or crowded into the small posterior cerebral fossa of affected fetuses. The lordotic elevation of the basichondrocranium is also responsible for the reduction of the pontine flexure and the increased angle of the cervical flexure of the hindbrain found in these fetuses. All of these neurological anomalies, which are characteristic and diagnostic of clinical ACm as well, are considered here to be secondary to the axial skeletal defects rather than primary abnormalities, as is generally believed. The peculiar type of protrusion of the odontoid process into the cranial cavity found in fetuses with ACM, as well as in those with cranioschisis aperta and occulta, is also considered to be caused by the slight depression of the underdeveloped basioccipital and therefore, comparable to the so-called basilar impression often described in clinical ACM. This study has emphasized various developmental features which are closely related with the morphogenesis of ACM, including: the somitic origin of the occipital bone, and the late growth of the cerebellum which is predominantly postnatal in almost all experimental animals. It has been pointed out that some developmental defects involving the occipital bone and the caudal vertebral column, such as those which characterize ACM type II, may be more closely related than previously recognized. It has been also pointed out that the so-called cerebellar herniation into the cervical spinal canal described in the human disease represents a late addition to this disorder which is related to the relatively late growth of the cerebellum...

Dose-response relationships of retinol in production of the Arnold-Chiari malformation.

A single oral dose of 5000, 10 000, 15 000, 20 000 or 30 000 I.U. vitamin A alcohol (retinol) on the eighth day of gestation in the pregnant hamster resulted in the production of the Arnold-Chiari malformation types I and II in 0, 6.6, 57, 56 and 85%, respectively, of all fetuses examined. The pattern and severity of the malformations of the chondrocranium and viscerocranium changed as the dose of retinol was increased. The smallest dose of retinol used in the present study which induced gross terata in hamsters was approximately 11 times greater than the highest oral daily dose of retinol used in clinical cancer chemoprevention trials.

Reduction in neural injury with earlier delivery in a mouse model of congenital myelomeningocele: laboratory investigation.

OBJECT: The authors undertook this study to assess the effect of preterm delivery with respect to neural protection in a congenital myelomeningocele (MMC) mouse model. METHODS: After confirmation of pregnancy in 15 female mice, a congenital MMC model was produced by administration of retinoic acid on the 7th day of gestation. The pregnant mice underwent cesarean sections on Days 15 (n = 5, Group E15), 17 (n = 5, Group E17), and 19 (n = 5, Group E19). Histological analyses were conducted on the lumbar defect and on the craniocervical junction in all fetuses with MMC. RESULTS: Fetuses in Group E19 showed the most significant injury to neural tissue of the spinal cord at the MMC area followed by those in Group E17, with Group E15 being the least affected. All groups exhibited a degree of Chiari malformation; Group E19 was the most affected, followed by Group E17, and Group E15 was the least affected. CONCLUSIONS: Development of both Chiari malformation and exposed spinal cord injury are progressive during gestation. Preterm delivery in this mouse model of congenital MMC may minimize the degree of injury to the spinal cord neural tissue and the degree of Chiari malformation.

[Arnold-Chiari malformation and syringomyelia in primary care. A case report]. / Malformación de Arnold-Chiari y siringomielia en atención primaria. A propósito de un caso.

Rare diseases, due to their epidemiological characteristics, and sometimes to the non-specific symptoms, are difficult to diagnose routinely at Primary Care Level. A case is presented of Arnold Chiari malformation in a young male patient with early insidious presentation (neck pain and sub-occipital headaches) consulting due to the emergence of new symptoms (paresthesias, muscular weakness, cervicobrachial and radiating lumbar pain, and headaches after mild exertion).

Retinoic acid induced myelomeningocele in fetal rats: characterization by histopathological analysis and magnetic resonance imaging.

The prevention of human neural tube defects by folic acid administration and the potential for fetal surgical intervention for myelomeningocele (MMC) have renewed interest in the molecular pathways and pathophysiology of spina bifida. Animal models for assessment of the early developmental biology and pathophysiology of this lesion are needed. The goal of this study was to develop and characterize a non-surgical rat model of MMC. Time-dated Sprague-Dawley rats were gavage fed different doses of retinoic acid (RA) dissolved in olive oil at E10 (maternal n = 55, fetal n = 505). Control animals received olive oil alone (maternal n = 20, fetal n = 265) or were untreated (maternal n = 5, fetal n = 63). Fetuses were analyzed by detailed histopathology and MRI. Overall, isolated MMC occurred in 60.7% (307/505) of RA-exposed fetuses and no controls. Histopathology confirmed the entire spectrum of severity observed in human MMC, ranging from exposure of the cord with intact neural elements to complete cord destruction. MRI of the brain of MMC fetuses confirmed structural changes similar to humans with Arnold-Chiari malformation, including downward displacement of the cerebellum to just above the foramen magnum and compression of the developing medulla into a small posterior fossa. In conclusion, the RA-induced rat model of MMC is developmentally and anatomically analogous to human MMC. This relatively efficient and cost-effective model of MMC should facilitate investigation of the developmental biology and pathophysiology of MMC, and may be useful for the evaluation of further strategies for prenatal treatment.

Fetal alcohol syndrome with Arnold-Chiari malformation: report of one case.

We report a rare case of fetal alcohol syndrome (FAS) with Arnold-Chiari malformation. The new-born had the typical facial abnormalities associated with FAS and the mother had a history of heavy drinking. CNS malformation, which is rarely seen in FAS, was also presented. The relationship between the developmental defects and maternal alcohol drinking are discussed together with a review of the literature.

Experimental spina bifida and associated malformations.

Seven litters and 17 near-term rats of mothers treated with teratogens during gestation were analyzed for concordance and discordance of congenital malformations of the central nervous system. In animals with spina bifida a firm association with Arnold-Chiari malformation was found but only in fetuses near term. Associations with aqueduct stenosis and hydrocephalus were poor. In general, the findings support the theory that the components of the spina bifida complex develop from a common teratogenic disturbance but independent from each other.

[Experimental production of myeloschisis associated with hindbrain crowding in the central nervous system of rat fetuses by a single intragastric administration of ethylenethiourea].

66 pregnant rats were divided into 9 groups according to gestation day 11 to 19. These pregnant rats were subjected to a single intragastric administration of ethylenethiourea (ETU) and cesarian sectioned on day 20. No dam died following the ETU treatment, but the rate of fetal death was as high as 21.2% on day 11, followed by a gradual decrease in the fetal death rate thereafter. The rate of production of various types of externally visible malformations was 100% except in the fetuses of dams treated with ETU on gestation day 19. The important results were as follows. (I) Fetuses of dams treated with ETU from gestation day 11 were found to suffer from a high incidence of myeloschisis associated with hindbrain crowding. (II) Exencephaly and an abnormally enlarged head with occipital bossing due to herniation of the mesencephalic tectum, with and without dilatation of the mesencephalic and 4th ventricle, were induced among the fetuses of dams given ETU at gestation day 12 and 13. (III) Various degrees of hydranencephaly and dysgenic hydrocephalus were found among the fetuses of dams treated with ETU from gestation days 14 to 18. The above results suggest that ETU may be a useful agent for the production of congenital malformations in the rat.

Transplacental induction of myeloschisis associated with hindbrain crowding and other malformations in the central nervous system in Long-Evans rats.

Nine groups of 66 pregnant rats, grouped by gestation days 11 to 19, were subjected to a single, intragastric administration of ethylenethiourea (ETU). Cesarean section was performed on gestation day 20. No dam died following the ETU treatment, although a mortality as high as 21.2% was noted among the fetuses in this group; the remaining live fetuses were found to suffer from a high incidence of myeloschisis associated with hindbrain crowding. Exencephaly and abnormally enlarged head with occipital bossing due to the herniation of the mesencephalic tectum, with and without dilation of the mesencephalic and 4th ventricles, were induced among the fetuses of the dams given ETU at gestation days 12 and 13. Various degrees of hydranencephaly and dysplastic hydrocephalus were found among the fetuses of dams treated by ETU from gestation days 14 to 18. From the histological features of these malformations of the central nervous system (CNS), a possible mechanism in the induction of myeloschisis with hindbrain crowding induced by ETU is discussed, and compared with the previously reported similar malformations induced by trypan blue.

The relationship between hydrocephalus and Chiari type II malformation in the experimental rat fetuses with Arnold-Chiari malformation.

Spina bifida, Chiari type II malformation, cerebral aqueduct stenosis and hydrocephalus are the most frequent association anomalies in the congenital malformation of the central nervous system (Warkany et al., 1958). They are potentially treatable and of clinical importance. But the relationship between hydrocephalus and Chiari type II malformation is still a controversial subject. A single oral dose of 240 mg/kg of ethylenethiourea (ETU) was given to Sprague Dawley (SD) rats on the 11th day of gestation. Fetuses were removed in the 20th day of gestation by cesarean sections; high incidence of spinal dysraphism associated with hindbrain crowding was found in these fetuses. They are similar to Arnold-Chiari malformation in humans. We used these experimental models to analyze the relationship between hydrocephalus and Chiari type II malformation. From the present investigation, no hydrocephalus or cerebral aqueduct stenosis was found in the experimental rat fetuses with the Arnold-Chiari malformation. So we do not consider the hydrodynamic theory that Chiari type II malformation was induced by increasing intracranial pressure in hydrocephalus. Hydrocephalus in the Arnold-Chiari malformation may not be the primary disorder but seems to be caused by plugging the foramen magnum in Chiari type II malformation. So the cerebrospinal fluid in the spinal subarachnoid space can not move upward to the cranial subarachnoid space for absorption to venous return. Cerebral aqueduct stenosis may be secondarily compressed by hydrocephalus and not be the primary development anomaly or acquired occlusion due to gliosis. This is in accord with the theory proposed by Russell and Donald (1935).(ABSTRACT TRUNCATED AT 250 WORDS)

Basilar invagination and mid-line skeletal abnormalities due to in utero exposure to phenytoin.

A case of basilar invagination which is thought to have arisen from the patient's intrauterine exposure to phenytoin is presented. The patient was treated surgically by foramen magnum decompression and occipito-cervical fusion, and by transoral resection of the clivus. His symptoms of brain stem compression were alleviated and the role of phenytoin in the production of his craniocervical abnormality is discussed.

Arnold-Chiari-like malformation associated with a valproate model of spina bifida in the rat.

The brains of rat fetuses exposed to saline and valproic acid (VA: 600 mg/kg or 1,200 mg/kg) at 10 days of gestation were examined for structural changes similar to that seen for the Arnold-Chiari malformation (ACM) in humans. Only fetuses exposed to the 1,200-mg/kg level VA demonstrated spina bifida (SB) type widening of the vertebral arch when compared to saline treated animals. When compared to controls, both 600-and 1,200-mg/kg VA animals demonstrated microencephaly. The brains of treated animals demonstrated alterations in their angular morphology such that the cerebellum was displaced toward the foramen magnum in a manner akin to human ACM. These findings indicate that valproate-induced SB in the rat more closely approximates SB in humans than was previously appreciated and provides a model for experimental study of both SB and ACM.